Oncogenesis最新文献

Pleural mesothelioma (PM) is an aggressive, asbestos-linked cancer with limited treatment options and a poor prognosis. Lactate dehydrogenase B (LDHB) converts lactate to pyruvate, and its silencing reduces mitochondrial metabolism, particularly nucleotide synthesis. However, whether and a role of LDHB in PM is unclear. This study aimed to investigate the effects of silencing LDHB in PM cells and their response to chemotherapy. LDHB was silenced using siRNA transfection and inducible shRNA constructs. Proliferation, colony formation, and cell viability were assessed, while DNA damage was analyzed through ɣH2AX levels. Compared to normal mesothelial cells, LDHB was highly expressed in PM cell lines. LDHB inhibition significantly reduced proliferation, cell viability, and colony formation, indicating its crucial role in PM cells. Additionally, LDHB silencing significantly increased nuclear DNA damage accumulation as indicated by elevated ɣH2AX levels, which was reversed by nucleotide supplementation. In vivo, LDHB inhibition reduced tumor growth and enhanced cisplatin's therapeutic efficacy. LDHB silencing increased ɣH2AX levels, which were further elevated with cisplatin treatment. Our results highlight LDHB as a novel therapeutic target in PM, where its inhibition induces DNA damage and improves the efficacy of cisplatin therapy.

The oncogenic BRAF(V600E) mutation activates the ERK1/2 pathway and is detected in 10% of human colorectal cancers (CRCs) where it is associated with poor prognosis. Inhibitors of BRAF have shown only modest efficacy in patients with CRC due to intrinsic drug resistance. We studied the CDK2/CDK9 inhibitor, fadraciclib, alone and in combination with the BRAF inhibitor encorafenib in isogenic human RKO CRC cells with two, one, or no BRAF^V600E alleles (RKO^+/+, A19^+/-, T29^-/-) and in BRAF wild-type HCT-116 cells, including Bax knockout HCT-116^Bax-/- cells. Treatment with fadraciclib was shown to suppress MCL-1 and phospho-MCL-1 (Ser64), induce a Bax-dependent apoptosis, and inhibit colony formation in a BRAF gene dose-dependent manner. Fadraciclib decreased phosphorylation of RNA polymerase II, indicating suppression of RNA transcription. The tumor growth inhibitory effect of fadraciclib plus encorafenib was synergistic. Fadraciclib decreased Rb phosphorylation, inhibited cell cycle progression, and promoted DNA damage as evidenced by cleavage of PARP, increased pH2AX (ser139), and activation of p53. In RKO^+/+ versus A19^+/- or T29^-/- cells, drug treatment was associated with greater suppression of p-Rb and inhibition of apoptosis and the cell cycle. In a zebrafish xenograft model, fadraciclib plus encorafenib significantly reduced tumor size, concurrent with increased caspase-3 activation. In human CRCs, BRAF mutation was associated with overexpression of CDK2, and CDK9 overexpression was associated with worse patient survival. In conclusion, fadraciclib depletes MCL-1 to potentiate apoptosis and, combined with encorafenib, synergistically suppresses tumor cell growth in a BRAF^V600E gene dose-dependent manner. These data suggest a novel therapeutic strategy in CRCs with BRAF^V600E.

Squamous cell carcinoma (SCC) poses a significant global health challenge due to the lack of effective treatments. Boron neutron capture therapy (BNCT), a targeted particle therapy, has shown promising results in various cancers. SLC7A5, a transporter of essential amino acids and boronophenylalanine (BPA) used in BNCT, emerges as a potential therapeutic target. However, its expression across different histological subtypes and the role of SLC7A5 inhibition in developing drug resistance to BPA-BNCT remain poorly understood. Our study reveals elevated SLC7A5 expression in most SCCs, particularly in lung squamous cell carcinoma (LUSC), where it is significantly higher compared to other lung cancer subtypes. Increased SLC7A5 expression and a higher tumor-to-normal (T/N) ratio in LUSC are associated with poor patient prognosis. SLC7A5 knockdown in LUSC cells reduces colony formation and induces apoptosis. RNA-seq analysis of SLC7A5 knockout LUSC cells shows downregulated mTORC1 signaling, reduced expression of other amino acid transporters, and upregulated autophagy genes, indicating a potential cancer metabolic shift. Furthermore, SLC7A5 knockout LUSC cells demonstrate resistance to BPA-BNCT but sensitivity to the autophagy inhibitor chloroquine. Post-BPA-BNCT treatment, surviving wild-type LUSC cells exhibit reduced SLC7A5 levels and increased sensitivity to chloroquine, highlighting a vulnerability in BPA-BNCT-resistant cells. Our findings elucidate the interplay between SLC7A5, mTOR signaling, and autophagy pathways, providing insights into potential strategies to overcome drug resistance in BPA-BNCT therapy.

BCL-XL is a crucial anti-apoptotic protein that supports survival of intestinal cells during the progression and in established colorectal cancer (CRC). While targeting BCL-XL with BH3 mimetics is effective, its significant toxicity highlights the need for alternative approaches. Importantly, the early steps in intestinal transformation are marked by a competition between normal and transformed stem cells in which the mutant cells gain a supercompetitive advantage due to the secretion of WNT inhibitors. Using multiple human and murine CRC models, we revealed that GSK-3 inhibition strongly sensitized to BH3 mimetic-induced killing. As expected, GSK-3 inhibition significantly upregulated the WNT pathway, but also led to marked enhancement of BH3 mimetic-induced apoptosis, as measured by mitochondrial BAX aggregation, Caspase-3 activation and Propidium Iodide exclusion. Furthermore, GSK-3 inhibition provided an advantage to wild-type intestinal organoids in competition with APC-mutant counterparts due to reactivation of the WNT pathway. More strikingly, combining GSK-3 and BCL-XL inhibition profoundly affected the supercompetition APC-mutant intestinal cells exert over the wild-types. In effect, the combination therapy enhanced the competitive fitness of wild-type cells and resulted in the killing of APC-mutant organoids, pointing to a novel combination therapy that can be further exploited in the treatment of adenomas and CRC.

It is well established that EZH2, a lysine methyltransferase, is upregulated in most aggressive cancers, highlighting the importance of EZH2 in cancer progression. Recent research has shown that metabolic reprogramming is pivotal in various biological processes, including cancer. Despite this, evidence of EZH2's role in regulating cancer metabolism remains limited. Our study reveals a negative correlation between EZH2 and HMGCS2, a gene belonging to the HMG-CoA synthase, in prostate and breast cancers. Interestingly, HMGCS2 is inversely related to cancer progression and prognosis in these cancers. Furthermore, HMGCS2 is epigenetically repressed by EZH2 both in vitro and in vivo. Notably, restored EZH2 reduces the elevated HMGCS2 levels observed upon EZH2 depletion. Overexpression of HMGCS2 decreases tumorigenesis in both prostate and breast cancers. Additionally, β-hydroxybutyrate (BHB), a downstream metabolite of HMGCS2, impedes prostate cancer progression by targeting EZH2 via direct protein-compound interaction-mediated protein degradation. More importantly, the ketone drink of BHB administration dramatically reduces tumor size and weight in a therapy-resistant, castration-resistant prostate cancer patient-derived xenograft model. Combining a ketone drink with FDA-approved drugs enzalutamide and Tazemetostat further suppresses tumor progression. Overall, the EZH2-HMGCS2-BHB regulatory network plays a critical role in the progression of prostate cancer, and a ketone drink is a novel therapeutic tool for patients with aggressive prostate cancer.

Biomarkers that predict disease progression may assist in the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. This study aimed to investigate the role of collagen type IV alpha 6 (COL4A6) in cell invasiveness, tumor formation, chemoresistance, and the prognostic impact of COL4A6 expression in ovarian cancer. COL4A6 regulated discoidin domain receptor 1 (DDR1)/p-DDR1 expression through the binding of E2F transcription factor 1 (E2F) to its putative DDR1 promoter binding site, suggesting that the E2F-DDR1 axis is upregulated by COL4A6. Pharmacological inhibition of DDR1 abrogated COL4A6-dependent cell invasiveness and chemoresistance. COL4A6 regulated cell invasion via the E2F1/DDR1/focal adhesion kinase axis; in contrast, COL4A6 regulated cell sensitivity to cisplatin via the DDR1/nuclear factor-kappa B axis. DDR1-IN-1 increased cell sensitivity to cisplatin, synergized with cisplatin to suppress the invasive ability and oncogenic potential of ovarian cancer cells, and decreased tumor formation in mouse xenografts. High COL4A6 mRNA levels were associated with advanced disease stages and poor chemotherapy response. The 5-year recurrence-free and overall survival rates were significantly lower in patients with high tissue COL4A6 mRNA expression levels than in those with low expression levels. COL4A6 may promote tumor aggressiveness and chemoresistance via the E2F/DDR1 axis, and COL4A6 expression can predict clinical outcomes in patients with ovarian cancer. DDR1 should be targeted in patients with COL4A6-positive tumors.

Lipid droplet-associated hydrolase (LDAH) is a lipid hydrolase abundantly expressed in adipose and ovarian tissues and macrophages. However, LDAH's functions in ovarian cancer are largely unknown. Analysis of publicly available patient datasets showed decreased LDAH expression in advanced stages of ovarian cancer, and low LDAH levels were associated with poor survival outcomes in ovarian cancer patients. Consistently, knockdown (KD) of LDAH in human ovarian cancer cell lines increased tumor cell proliferation but decreased endoplasmic reticulum (ER) stress and apoptosis upon cisplatin treatment. In addition, compared to scrambled control, LDAH KD ovarian cancer cells showed smaller lipid droplets (LDs), decreased triacylglycerol (TAG) content, and increased expression of adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1 A (CPT1A), and phospho-NF-kB. Our xenograft studies also showed increased tumor growth, increased ATGL expression, and decreased apoptosis after cisplatin treatment in LDAH KD tumors. ATGL overexpression increased cisplatin resistance and expression of CPT1A and phospho-NF-kB, whereas treatment of LDAH KD cells with an ATGL inhibitor attenuated the phenotype. Lastly, we observed that high ATGL levels were associated with shorter survival in ovarian cancer patients. Collectively, our results suggest that ovarian cancer cells downregulate LDAH expression, leading to enhanced ATGL-mediated TAG hydrolysis and increased tumor growth and chemoresistance.

Extracellular vesicles (EVs) play a pivotal role in intercellular communication and are closely linked to cancer progression and metastasis. Our previous studies have shown that gastric cancer cell-derived EVs can promote tumor metastasis by increasing the permeability of the endothelial barrier. However, it remains unclear which effector molecule in the EV structure is the key factor of EV-mediated tumor metastasis and the underlying molecular mechanism. In this study, we found that CD147 is a key molecule highly expressed in gastric cancer-derived EVs and confirmed the role of CD147-high EVs from gastric cancer cells in promoting endothelial dysfunction and tumor metastasis. Our results showed that CD147-high EVs activated the VEGF/AKT/eNOS/NO and AKT/mTOR/p70S6K signaling pathways, leading to endothelial cytoskeletal reorganization and internalization of VE-cadherin, which significantly compromised endothelial barrier integrity, increased vascular leakage, enhanced transendothelial migration of tumor cell, and promoted the formation of metastatic tumors. Furthermore, detection of CD147 levels in gastric cancer tissues and plasma EVs indicated that high CD147 expression was associated with advanced tumor stage, poor prognosis, and reduced survival. Our findings suggest that CD147-high EVs are critical mediators of tumor-endothelial interactions and potential diagnostic and prognostic biomarkers for gastric cancer. Their potential as therapeutic targets for gastric cancer is underscored. This figure illustrates the proposed mechanism by which CD147-high gcEVs promote tumor metastasis. CD147-high EVs are released from gastric cancer cells and interact with endothelial cells in the tumor microenvironment. Upon uptake by endothelial cells, CD147-high gcEVs activate the key signaling pathways, including the VEGF/AKT/eNOS/NO and AKT/mTOR/p70S6K pathway, which collectively facilitate the metastatic potential of gastric cancer cells by promoting endothelial cell dysfunction and increasing vascular permeability.

Head and neck squamous cell carcinoma (HNSCC) remains a prevalent and challenging cancer to treat due to its genetic heterogeneity. Cisplatin resistance is one of important causes in treatment failure of locally advanced HNSCC. ONC201, a selective dopamine receptor D2 antagonist and mitochondrial ClpP agonist, has emerged as a potential antitumor agent in various malignancies. This study explores the therapeutic potential of ONC201, alone and in combination with cisplatin, in both cisplatin-sensitive and -resistant HNSCC cells, with an emphasis on endoplasmic reticulum (ER) stress-mediated apoptosis. A cisplatin-resistant HNSCC subline (OC2-CR1) was developed via long-term drug exposure. The treatment effectiveness of ONC201 alone and cisplatin in combination on cell viability, DNA damage, reactive oxygen species (ROS) production, and stress response markers were evaluated. ONC201 exhibited potent cytotoxicity in both cisplatin-sensitive and -resistant HNSCC cells, retaining efficacy in OC2-CR1 cells. Combined treatment with ONC201 and cisplatin demonstrated synergistic inhibition of proliferation and migration, with enhanced induction of apoptosis. Mechanistically, ONC201 induced ER stress-mediated cell death via ATF4/CHOP signaling in cisplatin-sensitive cells, while ATF3/CHOP predominated in resistant cells. In vivo, combination therapy significantly suppressed tumor growth in xenograft models, including cisplatin-resistant tumors, without inducing toxicity. Immunohistochemical analysis confirmed activation of CHOP in tumor tissues. Furthermore, clinical correlation revealed that low CHOP expression in OSCC patients was associated with increased recurrence risk and inferior recurrence-free survival significantly. This study provides compelling evidence that ONC201 enhances cisplatin efficacy through distinct, stress-mediated apoptotic pathways in HNSCC. The ability of ONC201 to overcome cisplatin resistance and its synergistic antitumor effects highlight its promise as a candidate for combination therapy. These findings support the translational potential of targeting the ATF3/ATF4/CHOP axis to improve outcomes in patients with cisplatin resistant HNSCC.

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) functions as an oncogene in colorectal cancer (CRC), promotes the progression of CRC, and is associated with poor prognosis in patients. Studies have found that NUCKS1 promotes tumor cell metastasis, yet its role in CRC invasion and metastasis remains unclear. Our findings revealed higher NUCKS1 expression in metastatic CRC compared to non-metastatic samples. Upregulation of NUCKS1 expression promoted the migration and invasion of CRC cells, while knockdown of NUCKS1 significantly inhibited the migration and invasion of CRC cells. Mechanistically, NUCKS1 was initially found to upregulate HDAC2 expression by inhibiting the lysosomal pathway, activating AKT, and thus promoting CRC invasion and metastasis. Moreover, HDAC2 inhibitor Santacruzamate A or AKT inhibitor LY294002 rescued the migration and invasion of CRC cells caused by NUCKS1 overexpression. In vivo, by injecting CRC cells into the tail vein of a nude mouse model, we found that overexpression of NUCKS1-induced lung and liver metastasis was suppressed by HDAC2 knockdown or intraperitoneal administration of the HDAC2 inhibitor Santacruzamate A. Meanwhile, AKT inhibitor LY294002 significantly inhibited lung and liver metastasis caused by overexpression of HDAC2. The expression levels of NUCKS1, HDAC2, and phosphorylated AKT were significantly positively correlated in human CRC tissues. These findings suggest that NUCKS1 contributes to CRC invasion and metastasis by stabilizing HDAC2 and activating AKT, highlighting NUCKS1 and HDAC2 as potential therapeutic targets for CRC.