S. Tsuyuki, A. Yamaguchi, N. Senda, Yukiko Kawata, K. Kawaguchi
Neoadjuvant chemotherapy (NAC) has been the standard therapy for breast cancer; however, whether sentinel lymph node biopsy (SLNB) should be performed after NAC in clinically node-positive patients is controversial. The indocyanine green (ICG)-fluorescence SLNB method (ICG-SLNB) provides a high identification rate as well as the ability to visualize lymphatic pathways, and previous studies have investigated the lymphatic pathways to sentinel lymph nodes (sentinel lymphatic pathways) using ICG- fluorescence method. In this study, we used ICG-SLNB to compare the sentinel lymphatic pathways before and after NAC to investigate whether they were affected by chemotherapy. Although the locations of the sentinel lymph nodes were unchanged, NAC did alter 42.8% of the sentinel lymphatic pathway routes. Our data indicate that SLNB after NAC can still detect the sentinel lymph nodes regardless of the presence or absence of metastasis. Since the false negative rates of SLNB after NAC for node-positive patients is higher than that for node-negative patients according to meta-analyses, further investigation is required to determine whether to perform SLNB after NAC for node-positive patients.
{"title":"Effect of neoadjuvant chemotherapy on lymphatic pathways leading to sentinel lymph nodes in breast cancer","authors":"S. Tsuyuki, A. Yamaguchi, N. Senda, Yukiko Kawata, K. Kawaguchi","doi":"10.14800/CCM.850","DOIUrl":"https://doi.org/10.14800/CCM.850","url":null,"abstract":"Neoadjuvant chemotherapy (NAC) has been the standard therapy for breast cancer; however, whether sentinel lymph node biopsy (SLNB) should be performed after NAC in clinically node-positive patients is controversial. The indocyanine green (ICG)-fluorescence SLNB method (ICG-SLNB) provides a high identification rate as well as the ability to visualize lymphatic pathways, and previous studies have investigated the lymphatic pathways to sentinel lymph nodes (sentinel lymphatic pathways) using ICG- fluorescence method. In this study, we used ICG-SLNB to compare the sentinel lymphatic pathways before and after NAC to investigate whether they were affected by chemotherapy. Although the locations of the sentinel lymph nodes were unchanged, NAC did alter 42.8% of the sentinel lymphatic pathway routes. Our data indicate that SLNB after NAC can still detect the sentinel lymph nodes regardless of the presence or absence of metastasis. Since the false negative rates of SLNB after NAC for node-positive patients is higher than that for node-negative patients according to meta-analyses, further investigation is required to determine whether to perform SLNB after NAC for node-positive patients.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"13 7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82615141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer cells present differential metabolism compared to normal cells. Multiple molecular mechanisms converge to alter cellular metabolism, and some of these include a process of metabolic reprogramming which provides advantages to tumor cells in energy generation, growth and proliferation. Tumor energy production is basically dependent on glucose driven to glycolysis (Warburg effect), but it also happens by means of fatty acids and glutamine metabolism. Among the current challenges in cancer therapy, the tumor cell resistance and the absence of selectivity of anti-cancer agents stand out. It has been already shown that polyphenols are able to exert differential effects on normal and tumor cells. However, the exact mechanisms of these actions are not fully understood. In our previous study, we showed that a polyphenols-rich extract (PE) from Araucaria angustifolia held a selective capacity to inhibit the proliferation of human larynx HEp-2 cancer cells with minimal cytotoxicity to normal epithelial cells. We hypothesized that the effect presented by PE have happened by reversing the “Warburg effect” on cancer cells and inhibiting the mitochondrial electron transport chain complex I activity along with ATP depletion on these cells. In this research highlight we will discuss the effects of the PE on mitochondrial metabolism and their possible role in the modulation of mitochondrial sirtuin 3 (SIRT3) on tumor (HEp-2) and normal (HEK-293) cells, which may help to clarify the tumor selectivity exhibited by polyphenols.
{"title":"Polyphenols-rich extract from Araucaria angustifolia: Differential mechanisms on cancer and normal cells","authors":"C. Branco, T. Rodrigues, É. Lima, M. Salvador","doi":"10.14800/CCM.858","DOIUrl":"https://doi.org/10.14800/CCM.858","url":null,"abstract":"Cancer cells present differential metabolism compared to normal cells. Multiple molecular mechanisms converge to alter cellular metabolism, and some of these include a process of metabolic reprogramming which provides advantages to tumor cells in energy generation, growth and proliferation. Tumor energy production is basically dependent on glucose driven to glycolysis (Warburg effect), but it also happens by means of fatty acids and glutamine metabolism. Among the current challenges in cancer therapy, the tumor cell resistance and the absence of selectivity of anti-cancer agents stand out. It has been already shown that polyphenols are able to exert differential effects on normal and tumor cells. However, the exact mechanisms of these actions are not fully understood. In our previous study, we showed that a polyphenols-rich extract (PE) from Araucaria angustifolia held a selective capacity to inhibit the proliferation of human larynx HEp-2 cancer cells with minimal cytotoxicity to normal epithelial cells. We hypothesized that the effect presented by PE have happened by reversing the “Warburg effect” on cancer cells and inhibiting the mitochondrial electron transport chain complex I activity along with ATP depletion on these cells. In this research highlight we will discuss the effects of the PE on mitochondrial metabolism and their possible role in the modulation of mitochondrial sirtuin 3 (SIRT3) on tumor (HEp-2) and normal (HEK-293) cells, which may help to clarify the tumor selectivity exhibited by polyphenols.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89723710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer is among the most common causes of death in the United States, second only to heart disease, and is initiated by a loss of cell cycle control resulting from the deregulation of oncogenes and/or tumor suppressor genes. Epigenetic changes, such as DNA methylation or histone modifications, are common in cancer cells leading to altered gene regulation and tumor progression. Recently, studies have identified aberrant DNA methyltransferase ( DNMT ) transcripts in cancer cells but not normal cells. Specifically, aberrant transcripts of DNMT3B have been shown to have a role in tumor progression including the ΔDNMT3B variants as well as DNMT3B7 . This review focuses on epigenetic changes caused by aberrant DNMT3B s in cancer and their role in tumor progression or suppression.
{"title":"The role of aberrant DNMT3Bs in tumor progression","authors":"Rabia Hameed, Stacey L Raimondi","doi":"10.14800/CCM.847","DOIUrl":"https://doi.org/10.14800/CCM.847","url":null,"abstract":"Cancer is among the most common causes of death in the United States, second only to heart disease, and is initiated by a loss of cell cycle control resulting from the deregulation of oncogenes and/or tumor suppressor genes. Epigenetic changes, such as DNA methylation or histone modifications, are common in cancer cells leading to altered gene regulation and tumor progression. Recently, studies have identified aberrant DNA methyltransferase ( DNMT ) transcripts in cancer cells but not normal cells. Specifically, aberrant transcripts of DNMT3B have been shown to have a role in tumor progression including the ΔDNMT3B variants as well as DNMT3B7 . This review focuses on epigenetic changes caused by aberrant DNMT3B s in cancer and their role in tumor progression or suppression.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84757357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna S. Sedukhina, Elayanambi Sundaramoorthy, Masaki Hara, T. Kumai, Ko Sato
Poly-ADP ribosylation polymerase (PARP) inhibition is a promising new strategy that specifically kills malignancies with mutation of BRCA genes. However, as in other agents, it is known that continuous treatment with PARP inhibitors generates acquired resistance in these tumors. In this review, we discuss about the potential mechanisms of acquired resistance to the PARP inhibition that is routed through up-regulation of the NF-κB signaling pathway and furthermore discuss about potential treatment options for malignancies that gain such resistance.
{"title":"Beyond resistance to PARP inhibition: Mechanisms and effective treatment options.","authors":"Anna S. Sedukhina, Elayanambi Sundaramoorthy, Masaki Hara, T. Kumai, Ko Sato","doi":"10.14800/CCM.821","DOIUrl":"https://doi.org/10.14800/CCM.821","url":null,"abstract":"Poly-ADP ribosylation polymerase (PARP) inhibition is a promising new strategy that specifically kills malignancies with mutation of BRCA genes. However, as in other agents, it is known that continuous treatment with PARP inhibitors generates acquired resistance in these tumors. In this review, we discuss about the potential mechanisms of acquired resistance to the PARP inhibition that is routed through up-regulation of the NF-κB signaling pathway and furthermore discuss about potential treatment options for malignancies that gain such resistance.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81811523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The enhanced permeability and retention effect of nanoparticles has become the gold standard principle for cancer drug delivery systems, holding the promise of safe, simple and effective therapy. Nevertheless, due to its poor clinical translation, many recent papers describe the limitations of this EPR effect. Hence, efforts should be provided to overcome these barriers allowing the enhancement of nanomedicines on the market. This communication reviews three main strategies to enhance the EPR effect: (i) the normalization of the tumor vasculature; (ii) the possibility to include collagenase or hyaluronidase into the tumor microenvironment to simultaneously improve the transport and reduce the interstitial fluid pressure and (iii) the increase of the tumor permeability using external or internal stimuli.
{"title":"Strategies to improve the EPR effect for the delivery of anti-cancer nanomedicines","authors":"F. Danhier, V. Préat","doi":"10.14800/CCM.808","DOIUrl":"https://doi.org/10.14800/CCM.808","url":null,"abstract":"The enhanced permeability and retention effect of nanoparticles has become the gold standard principle for cancer drug delivery systems, holding the promise of safe, simple and effective therapy. Nevertheless, due to its poor clinical translation, many recent papers describe the limitations of this EPR effect. Hence, efforts should be provided to overcome these barriers allowing the enhancement of nanomedicines on the market. This communication reviews three main strategies to enhance the EPR effect: (i) the normalization of the tumor vasculature; (ii) the possibility to include collagenase or hyaluronidase into the tumor microenvironment to simultaneously improve the transport and reduce the interstitial fluid pressure and (iii) the increase of the tumor permeability using external or internal stimuli.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88045212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protease nexin 1 (PN1), a member of serine protease inhibitors (SERPINs) family, is known for its ability to bind and inhibit a wide range of proteases. Recently, we have found that PN1 is able to induce prostate cancer cell undergoing apoptosis through a distinct mechanism of engaging uPA-uPAR complexes and the regulation of two independent downstream signaling cascades, leading to the repression of X-linked inhibitor of apoptosis protein (XIAP). In this process, PN1 expression reduces the expression of NF-κB signalling component p65 and thereby lessens xiap transcription. Alternately, PN1 activity can prevent the stability of XIAP by reducing XIAP phosphorylation at serine 87 via a blockade of AKT signaling. A combination of exogenous PN1 and TRAIL leads to a substantial growth lag in prostate cancer xenografts, indicating the potential of PN1 as a promising target for improving prostate cancer therapy. Furthermore, human prostate tissue arrays show inverse levels of PN1 and XIAP in tumor and normal prostate. Hence, the PN1-uPA regulatory axis may serve as an inducer of tumor cell apoptosis by modulating survival pathways, and therefore delay the tumor growth of prostate cancer.
蛋白酶连接蛋白1 (PN1)是丝氨酸蛋白酶抑制剂(SERPINs)家族的一员，以其结合和抑制多种蛋白酶的能力而闻名。最近，我们发现PN1能够通过参与uPA-uPAR复合物和调节两个独立的下游信号级联的独特机制诱导前列腺癌细胞发生凋亡，导致X-linked inhibitor of apoptosis protein (XIAP)的抑制。在这个过程中，PN1的表达降低了NF-κB信号元件p65的表达，从而减少了xiap的转录。另外，PN1活性可以通过阻断AKT信号通路，降低XIAP丝氨酸87的磷酸化，从而阻止XIAP的稳定性。外源性PN1和TRAIL的结合导致前列腺癌异种移植物的生长明显滞后，这表明PN1可能是改善前列腺癌治疗的一个有希望的靶点。此外，人类前列腺组织阵列显示PN1和XIAP在肿瘤和正常前列腺中呈反比水平。因此，PN1-uPA调控轴可能通过调节生存通路，作为肿瘤细胞凋亡的诱导剂，从而延缓前列腺癌肿瘤的生长。
{"title":"Protease nexin 1: A novel inducer of prostate tumor cell apoptosis","authors":"Yunchuan Ding, C. Mckee, R. Muschel, Danmei Xu","doi":"10.14800/CCM.812","DOIUrl":"https://doi.org/10.14800/CCM.812","url":null,"abstract":"Protease nexin 1 (PN1), a member of serine protease inhibitors (SERPINs) family, is known for its ability to bind and inhibit a wide range of proteases. Recently, we have found that PN1 is able to induce prostate cancer cell undergoing apoptosis through a distinct mechanism of engaging uPA-uPAR complexes and the regulation of two independent downstream signaling cascades, leading to the repression of X-linked inhibitor of apoptosis protein (XIAP). In this process, PN1 expression reduces the expression of NF-κB signalling component p65 and thereby lessens xiap transcription. Alternately, PN1 activity can prevent the stability of XIAP by reducing XIAP phosphorylation at serine 87 via a blockade of AKT signaling. A combination of exogenous PN1 and TRAIL leads to a substantial growth lag in prostate cancer xenografts, indicating the potential of PN1 as a promising target for improving prostate cancer therapy. Furthermore, human prostate tissue arrays show inverse levels of PN1 and XIAP in tumor and normal prostate. Hence, the PN1-uPA regulatory axis may serve as an inducer of tumor cell apoptosis by modulating survival pathways, and therefore delay the tumor growth of prostate cancer.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87158527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Spinophilin, a multifunctional intracellular protein, has attracted attention within the last years as a novel putative tumor suppressor protein. Recent studies have shown a reduction of spinophilin expression levels in various types of cancer, such as lung adenocarcinoma, ovarian cancer, and chronic myelogenous leukemia. Low expression of spinophilin was also associated with a higher malignant grade in some of these studies. Our own studies on hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), colorectal adenocarcinoma (CRC) and breast cancer explored the possible role of spinophilin as a proliferative trigger and potentially prognostic factor. We determined the spinophilin expression through immunohistochemistry, quantitative reverse transcriptase-PCR analysis, and used small interfering RNA (siRNA) or stably expressed shRNAs to disable spinophilin in order to investigate the cellular and molecular effects of reduced spinophilin expression. Statistical methods on appropriate cohorts were used to define the prognostic value and impact on clinical outcome of spinophilin expression levels in patients with HCC, HNSCC, or CRC and breast cancer. Spinophilin seems to play an important role as a crucial protein in cell cycle and proliferation, and thus our findings seems to prove this hypothesis derived from other types of cancer. In the cohorts studied, low expression of spinophilin was identified as an independent prognostic factor that indicates poor clinical outcome. In the past, various key molecules and molecular mechanisms highly impacted clinical practice and specific cancer treatment; therefore, novel factors are needed to improve the moderate survival rates of patients with HCC, HNSCC, and CRC. Taken together, spinophilin is a promising new pathophysiological factor and might be a useful novel biomarker for prognostic purposes.
{"title":"Spinophilin in human cancer–molecular mechanisms and clinical relevance","authors":"Edvin Mrsic, R. Wagle, M. Pichler","doi":"10.14800/CCM.816","DOIUrl":"https://doi.org/10.14800/CCM.816","url":null,"abstract":"Spinophilin, a multifunctional intracellular protein, has attracted attention within the last years as a novel putative tumor suppressor protein. Recent studies have shown a reduction of spinophilin expression levels in various types of cancer, such as lung adenocarcinoma, ovarian cancer, and chronic myelogenous leukemia. Low expression of spinophilin was also associated with a higher malignant grade in some of these studies. Our own studies on hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), colorectal adenocarcinoma (CRC) and breast cancer explored the possible role of spinophilin as a proliferative trigger and potentially prognostic factor. We determined the spinophilin expression through immunohistochemistry, quantitative reverse transcriptase-PCR analysis, and used small interfering RNA (siRNA) or stably expressed shRNAs to disable spinophilin in order to investigate the cellular and molecular effects of reduced spinophilin expression. Statistical methods on appropriate cohorts were used to define the prognostic value and impact on clinical outcome of spinophilin expression levels in patients with HCC, HNSCC, or CRC and breast cancer. Spinophilin seems to play an important role as a crucial protein in cell cycle and proliferation, and thus our findings seems to prove this hypothesis derived from other types of cancer. In the cohorts studied, low expression of spinophilin was identified as an independent prognostic factor that indicates poor clinical outcome. In the past, various key molecules and molecular mechanisms highly impacted clinical practice and specific cancer treatment; therefore, novel factors are needed to improve the moderate survival rates of patients with HCC, HNSCC, and CRC. Taken together, spinophilin is a promising new pathophysiological factor and might be a useful novel biomarker for prognostic purposes.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81065643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hydrophobic weak base chemotherapeutics are known to markedly accumulate in lysosomes via a mechanism based on protonation and entrapment known as lysosomal drug sequestration. We have recently shown that lysosomal compartmentalization of these anticancer drugs can prevent them from exerting their cytotoxic activity by abolishing accessibility to their target sites, resulting in multidrug resistance. Consistently, we as well as others have recently demonstrated that lysosomal sequestration of the receptor tyrosine kinase inhibitor sunitinib is a determinant of intrinsic resistance in human cancer cells. We specifically found that the number of sunitinib sequestering lysosomes tightly correlated with intrinsic resistance to sunitinib in various naive tumor cell lines of distinct tissue lineage. We further demonstrated that lysosomal accumulation of several hydrophobic weak base drugs triggers activation of lysosomal biogenesis via translocation of the master regulator TFEB from the cytoplasm to the nucleus. This resulted in activation of the Coordinated Lysosomal Expression and Regulation (CLEAR) gene network. This drug-induced activation of lysosomal biogenesis brought about a marked increase in lysosome number per cell. Here we demonstrate the role of alterations in the cytoplasm-to-lysosome pH gradient in lysosomal sequestration of anticancer drugs. We specifically show that MCF-7 breast cancer cells which display a markedly diminished cytoplasm-to-lysosome pH gradient due to both decreased lysosomal acidification and acidification of cytoplasmic pH, are devoid of hydrophobic weak base drug sequestration in lysosomes. The latter finding was of particular significance as MCF-7 cells were found to harbor a relatively high number of lysosomes per cell. We further show that disruption of lysosomal acidification using bafilomycin A1, an inhibitor of vacuolar H + ATPase (V-ATPase), prevents lysosomal drug sequestration when performed prior to hydrophobic weak base drug exposure. Moreover, such lysosomal alkalinization performed after lysosomal drug sequestration, results in massive drug release from lysosomes into the cytoplasm, hence restoring drug accessibility to the cellular target site. These findings have significant implications for the overcoming of lysosome-dependent cancer chemoresistance.
{"title":"The role of cytoplasmic-to-lysosomal pH gradient in hydrophobic weak base drug sequestration in lysosomes","authors":"B. Zhitomirsky, Y. Assaraf","doi":"10.14800/CCM.807","DOIUrl":"https://doi.org/10.14800/CCM.807","url":null,"abstract":"Hydrophobic weak base chemotherapeutics are known to markedly accumulate in lysosomes via a mechanism based on protonation and entrapment known as lysosomal drug sequestration. We have recently shown that lysosomal compartmentalization of these anticancer drugs can prevent them from exerting their cytotoxic activity by abolishing accessibility to their target sites, resulting in multidrug resistance. Consistently, we as well as others have recently demonstrated that lysosomal sequestration of the receptor tyrosine kinase inhibitor sunitinib is a determinant of intrinsic resistance in human cancer cells. We specifically found that the number of sunitinib sequestering lysosomes tightly correlated with intrinsic resistance to sunitinib in various naive tumor cell lines of distinct tissue lineage. We further demonstrated that lysosomal accumulation of several hydrophobic weak base drugs triggers activation of lysosomal biogenesis via translocation of the master regulator TFEB from the cytoplasm to the nucleus. This resulted in activation of the Coordinated Lysosomal Expression and Regulation (CLEAR) gene network. This drug-induced activation of lysosomal biogenesis brought about a marked increase in lysosome number per cell. Here we demonstrate the role of alterations in the cytoplasm-to-lysosome pH gradient in lysosomal sequestration of anticancer drugs. We specifically show that MCF-7 breast cancer cells which display a markedly diminished cytoplasm-to-lysosome pH gradient due to both decreased lysosomal acidification and acidification of cytoplasmic pH, are devoid of hydrophobic weak base drug sequestration in lysosomes. The latter finding was of particular significance as MCF-7 cells were found to harbor a relatively high number of lysosomes per cell. We further show that disruption of lysosomal acidification using bafilomycin A1, an inhibitor of vacuolar H + ATPase (V-ATPase), prevents lysosomal drug sequestration when performed prior to hydrophobic weak base drug exposure. Moreover, such lysosomal alkalinization performed after lysosomal drug sequestration, results in massive drug release from lysosomes into the cytoplasm, hence restoring drug accessibility to the cellular target site. These findings have significant implications for the overcoming of lysosome-dependent cancer chemoresistance.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90753331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The anti-apoptotic protein prothymosin alpha (PTMA) is overexpressed in various cancers, including hepatocellular carcinoma (HCC). Earlier studies have shown that PTMA blocks apoptosis in cancer cells by inhibiting caspase-9 activation and apoptosome formation. Our recent study shows that silencing of PTMA potentiates the mitochondria-dependent apoptosis pathway in sorafenib-treated HCC cells, leading to Bax translocation, pBad dephosphorylation, and cytochrome c release. Our findings also indicate that the pERK/c-Myc/Max/PTMA axis represents a newly identified target of sorafenib in chemotherapy against HCC.
{"title":"Sorafenib induces apoptosis in hepatocellular carcinoma cells by inhibiting c-Myc and prothymosin-alpha","authors":"Yi-Te Lin, C. Chao","doi":"10.14800/CCM.788","DOIUrl":"https://doi.org/10.14800/CCM.788","url":null,"abstract":"The anti-apoptotic protein prothymosin alpha (PTMA) is overexpressed in various cancers, including hepatocellular carcinoma (HCC). Earlier studies have shown that PTMA blocks apoptosis in cancer cells by inhibiting caspase-9 activation and apoptosome formation. Our recent study shows that silencing of PTMA potentiates the mitochondria-dependent apoptosis pathway in sorafenib-treated HCC cells, leading to Bax translocation, pBad dephosphorylation, and cytochrome c release. Our findings also indicate that the pERK/c-Myc/Max/PTMA axis represents a newly identified target of sorafenib in chemotherapy against HCC.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78759667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
It was once believed that tumor growth, progression, and metastasis were intrinsically driven by the tumor. Instead, recent research has demonstrated that a solid tumor is surrounded by a complex matrix of cells, particularly fibroblasts, which support and even promote tumor progression. This matrix of stromal cells, also known as the tumor microenvironment (TME), plays a critical role in cancer and may represent a novel therapeutic target. As such, understanding the complex nature of how the tumor initiates and maintains communication, or a "conversation", with the TME is the focus of current investigations. We have previously shown that the most prevalent mutation found in melanoma, BRAFV600E, results in increased expression and secretion of several growth factors, cytokines, and matrix metalloproteinases, including factors that are able to activate fibroblasts. Targeted inhibition of the BRAFV600E mutation resulted in a decrease of secreted proteins into the TME and suggests that targeting the tumor also modifies the TME. Overall, this work, in combination with several additional studies discussed herein, provides strong evidence for the potential therapeutic benefits of targeting the TME, particularly signaling pathways within the fibroblasts, in conjunction with the tumor. This approach may result in extended drug resistance free survival, reduction in metastasis, and improved cytotoxic drug delivery.
{"title":"Tumor talk: understanding the conversation between the tumor and its microenvironment.","authors":"Chery A Whipple","doi":"10.14800/ccm.773","DOIUrl":"https://doi.org/10.14800/ccm.773","url":null,"abstract":"<p><p>It was once believed that tumor growth, progression, and metastasis were intrinsically driven by the tumor. Instead, recent research has demonstrated that a solid tumor is surrounded by a complex matrix of cells, particularly fibroblasts, which support and even promote tumor progression. This matrix of stromal cells, also known as the tumor microenvironment (TME), plays a critical role in cancer and may represent a novel therapeutic target. As such, understanding the complex nature of how the tumor initiates and maintains communication, or a \"conversation\", with the TME is the focus of current investigations. We have previously shown that the most prevalent mutation found in melanoma, BRAF<sup>V600E</sup>, results in increased expression and secretion of several growth factors, cytokines, and matrix metalloproteinases, including factors that are able to activate fibroblasts. Targeted inhibition of the BRAF<sup>V600E</sup> mutation resulted in a decrease of secreted proteins into the TME and suggests that targeting the tumor also modifies the TME. Overall, this work, in combination with several additional studies discussed herein, provides strong evidence for the potential therapeutic benefits of targeting the TME, particularly signaling pathways within the fibroblasts, in conjunction with the tumor. This approach may result in extended drug resistance free survival, reduction in metastasis, and improved cytotoxic drug delivery.</p>","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"2 2","pages":"e773"},"PeriodicalIF":0.0,"publicationDate":"2015-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14800/ccm.773","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33223688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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