Journal of Cancer Prevention最新文献

The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) convened the "Translational Advances in Cancer Prevention Agent Development (TACPAD) Workshop on Immunomodulatory Agents" as a virtual 2-day workshop on September 13 to 14, 2021. The main goals of this workshop were to foster the exchange of ideas and potentially new collaborative interactions among leading cancer immunoprevention researchers from basic and clinical research and highlight new and emerging trends in immunoprevention. The workshop included an overview of the mechanistic classes of immunomodulatory agents and three sessions covering the gamut from preclinical to clinical studies. The workshop convened individuals working in immunology and cancer prevention to discuss trends in discovery and development of immunomodulatory agents individually and in combination with other chemopreventive agents or vaccines.

Given the high rates of incidence and mortality associated with pancreatic cancer (PanC), there is a need to develop alternative strategies to target PanC. Recent studies have demonstrated that fruits of bitter melon (Momordica charantia) exhibit strong anticancer efficacy against PanC. However, the comparative effects of different bitter melon varieties have not been investigated. This has important implications, given that several bitter melon cultivars are geographically available but their differential effects are not known; and that on a global level, individuals could consume different bitter melon varieties sourced from different cultivars for anti-PanC benefits. Considering these shortcomings, in the present study, comparative pre-clinical anti-PanC studies have been conducted using lyophilized-juice and aqueous-methanolic extracts of the two most widely consumed but geographically diverse bitter melon varieties (Chinese [bitter melon juice; BMJ] and Indian [bitter melon extract; BME] variants). We observed that both BMJ and BME possess comparable efficacy against PanC growth and progression; specifically, these preparations have the potential to (a) inhibit PanC cell proliferation and induce cell death; (b) suppress PanC tumor growth, proliferation, and induce apoptosis; (c) restrict capillary tube formation by human umbilical vein endothelial cells, and decrease angiogenesis in PanC tumor xenografts. Thus, given the comparable pre-clinical anti-PanC efficacy of bitter melon cultivars, the geographical non-availability of a certain cultivar should not be a limiting factor in selecting a variant for moving forward for future clinical use/clinical trials either as a preventive or a therapeutic alternative for targeting PanC.

Branched-chain amino acids (BCAAs), isoleucine, leucine and valine, are essential amino acids with vital roles in protein synthesis and energy production. We reviewed the fundamentals of BCAA metabolism in advanced cancer patients. BCAAs and various catabolic products act as signalling molecules, which activate mechanisms ranging from protein synthesis to insulin secretion. Recently, BCAA metabolism has been suggested to contribute to cancer progression. Of particular interest is the modulation of the mTOR activity by BCAAs. There are likely multiple pathways involved in BCAA metabolism implicated in carcinogenesis. Understanding the mechanism(s) underlying altered BCAAs metabolism will significantly advance the current understanding of nutrient involvement in carcinogenesis and direct future studies to unravel the significance of BCCA metabolites in tumor development and progression.

Ginger (Zingiber officinale) has traditionally been used as a treatment for inflammatory diseases in the Asian region. Recently, anti-inflammatory effects of steamed ginger extract (GGE03) have been reported, but its association with Helicobacter pylori (H. pylori)-induced gastritis has not been investigated. The purpose of this study was to assess the anti-inflammatory activity of GGE03 in H. pylori-infected gastric epithelial cells. Our studies revealed that the GGE03 suppressed the growth of H. pylori. GGE03 markedly reduced the expression of the H. pylori-induced pro-inflammatory cytokines including interleukin (IL)-8, TNF-α, IL-6, inducible NOS (iNOS) and IFN-γ. We also demonstrated that GGE03 treatment inhibited the H. pylori-activated NF-κB signaling pathway. In addition, the treatment with GGE03 significantly attenuated nitric oxide production and myeloperoxidase activity in H. pylori-infected gastric epithelial cells. These anti-inflammatory effects of GGE03 were more effective than ginger extract. Finally, we investigated the minimum effective concentration of GGE03 to inhibit H. pylori-induced inflammation. Our findings suggest that GGE03 not only inhibits the growth of H. pylori, but also attenuates H. pylori-induced inflammation.

Air pollutants are in the spotlight because the human body can easily be exposed to them. Among air pollutants, the particulate matter (PM) represents one of the most serious toxicants that can enter the human body through various exposure routes. PMs have various adverse effects and classified as severe carcinogen by International Agency for Research on Cancer. Their physical and chemical characteristics are distinguished by their size. In this review, we summarized the published information on the physicochemical characteristics and adverse effects of PMs on the skin, including carcinogenicity. Through comparisons of biological networks constructed from relationships discussed in the previous scientific publications, we show it is possible to predict skin cancers and other disorders from particle-size-specific signaling alterations of PM-responsive genes. Our review not only helps to grasp the biological association between ambient PMs and skin diseases including cancer, but also provides new approaches to interpret chemical-gene-disease associations regarding the adverse effects of these heterogeneous particles.

Dioscin (DS), a steroidal saponin, has been shown to have anti-cancer activity by exerting antioxidant effects and inducing apoptosis. However, the anti-cancer activity of DS in breast cancer-derived stem cells is still controversial. The purpose of this study was to evaluate the effects of DS on migration, invasion, and colony formation in MDA-MB-231 and MCF-7 cell lines and the mechanism by which it inhibits proliferation of breast cancer stem-like cells after inducing differentiation into breast cancer stem cells. DS treatment significantly reduced cellular migration, invasion, and colony formation in MDA-MB-231 and MCF-7 cells. During the differentiation process that induced manifestation of breast cancer stem-like cells, DS significantly inhibited mammosphere formation in a dose-dependent manner and increased the expression of p53 and p21 in breast cancer stem-like cells, reducing the expression of cdc2 and cyclin B1 in MDA-MB-231 cells and cyclin D, cyclin E, CDK4, and CDK2 in MCF-7 cells. Interestingly, DS treatment induced G2/M and G0/G1 cell cycle arrest in the MDA-MB-231 and MCF-7 cells, respectively. DS also increased the phosphorylation of p38 and decreased the expression levels of p-AKT and p-mTOR. These results suggest that DS regulates the p38 mitogen-activated protein kinase and AKT/mTOR signaling pathways to reduce the proliferation of breast cancer stem-like cells through cell cycle arrest. Therefore, these findings suggest that DS may serve as a potential treatment candidate targeting breast cancer stem cells.

STAT3 plays a prominent role in proliferation and survival of tumor cells. Thus, STAT3 has been considered to be a prime target for development of anti-cancer therapeutics. The electrophilic cyclopentenone prostaglandin,15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) has been well recognized for its capability to modulate intracellular signaling pathways involved in cancer cell growth and progression. We previously reported that 15d-PGJ₂ had potent cytotoxicity against harvey-ras transformed human mammary epithelial cells through direct interaction with STAT3. In this study, we have attempted to verify the inhibitory effects of 15d-PGJ₂ on STAT3 signaling in human breast tumor cells. The triple negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468 displaying constitutive phosphorylation of STAT3 on the tyrosine 705 (Tyr705) residue, underwent apoptosis upon inhibition of STAT3 by 15d-PGJ₂. In contrast, estrogen receptor positive MCF-7 breast cancer cells that do not exhibit elevated STAT3 phosphorylation were much less susceptible to 15d-PGJ₂-induced apoptosis as assessed by PARP cleavage. Furthermore, 15d-PGJ₂ inhibited interleukin-6-induced tyrosine phosphorylation of STAT3 in LNCaP cells. According to molecular docking studies, 15d-PGJ₂ may preferentially bind to the cysteine 259 residue (Cys259) present in the coiled-coil domain of STAT3. Site-directed mutagenesis of STAT3 identified Cys259 to be the critical amino acid for the 15d-PGJ₂-induced apoptosis as well as epithelial-to-mesenchymal transition. Taken together, these findings suggest STAT3 inactivation through direct chemical modification of its Cys259 as a potential therapeutic approach for treatment of triple negative breast cancer treatment.

Exposure of the skin to solar UV radiation leads to inflammation, DNA damage, and dysregulation of cellular signaling pathways, which may cause skin cancer. Photochemoprevention with natural products is an effective strategy for the control of cutaneous neoplasia. Polyphenols have been proven to help prevent skin cancer and to inhibit the growth of cancer stem cells (CSCs) through epigenetic mechanisms, including modulation of microRNAs expression. Thus, the current study aimed to assess the effect of polyphenol enriched blueberry preparation (PEBP) or non-fermented blueberry juice (NBJ) on expression of miRNAs and target proteins associated with different clinicopathological characteristics of skin cancer such as stemness, motility, and invasiveness. We observed that PEBP significantly inhibited the proliferation of skin CSCs derived from different melanoma cell lines, HS 294T and B16F10. Moreover, PEBP was able to reduce the formation of melanophores. We also showed that the expression of the CD133⁺ stem cell marker in B16F10 and HS294T cell lines was significantly decreased after treating the cells with PEBP in comparison to the NBJ and control groups. Importantly, tumor suppressors' miR-200s, involved in the regulation of the epithelial-to-mesenchymal transition and metastasis, were strikingly upregulated. In addition, we have shown that a protein target of the tumor suppressor miR200b, ZEB1, was also significantly modulated. Thus, the results demonstrates that PEBP possesses potent anticancer and anti-metastatic potentials and may represent a novel chemopreventative agent against skin cancer.

F-box proteins, consisting of 69 members which are organized into the three subclasses FBXW, FBXL, and FBXO, are the substrate specific recognition subunits of the SKP1-Cullin 1-F-box protein E3 ligase complex. Although βTrCP 1 and 2, members of the FBXW subfamily, are known to regulate some protein stability, molecular mechanisms by which these proteins can recognize proper substrates are unknown. In this study, it was found that βTrCP1 showed strong interaction with members of mitogen-activated protein kinases. Although extracellular signal-regulated kinase (ERK) 3, p38β, and p38δ showed weak interactions, ERK2 specifically interacted with βTrCP1 as assessed by immunoprecipitation. In interaction domain determination experiments, we found that ERK2 interacted with two independent ERK docking sites located in the F-box domain and linker domain, but not the WD40 domain, of βTrCP1. Notably, mutations of βTrCP1 at the ERK docking sites abolished the interaction with ERK2. βTrCP1 underwent phosphorylation by EGF stimulation, while the presence of the mitogen-activated protein kinase kinases inhibitor U0126, genetic silencing by sh-ERK2, and mutation of the ERK docking site of βTrCP1 inhibited phosphorylation. This inhibition of βTrCP1 phosphorylation resulted in a shortened half-life and low protein levels. These results suggest that ERK2-mediated βTrCP1 phosphorylation may induce the destabilization of βTrCP1.

Pancreatic stellate cells (PSCs) are activated by inflammatory stimuli, such as TNF-α or viral infection. Activated PSCs play a crucial role in the development of chronic pancreatitis. Polyinosinic-polycytidylic acid (poly (I:C)) is structurally similar to double-stranded RNA and mimics viral infection. Docosahexaenoic acid (DHA) exhibits anti-inflammatory activity. It inhibited fibrotic mediators and reduced NF-κB activity in the pancreas of mice with chronic pancreatitis. The present study aimed to investigate whether DHA could suppress cytokine expression in PSCs isolated from rats. Cells were pre-treated with DHA or the antioxidant N-acetylcysteine (NAC) and stimulated with TNF-α or poly (I:C). Treatment with TNF-α or poly (I:C) increased the expression of monocyte chemoattractant protein 1 (MCP-1) and chemokine C-X3-C motif ligand 1 (CX3CL1), which are known chemoattractants, and enhanced intracellular and mitochondrial reactive oxygen species (ROS) production and NF-κB activity, but reduced mitochondrial membrane potential (MMP). Increased intracellular and mitochondrial ROS accumulation, cytokine expression, MMP disruption, and NF-κB activation were all prevented by DHA in TNF-α- or poly (I:C)-treated PSCs. NAC suppressed TNF-α- or poly (I:C)-induced expression of MCP-1 and CX3CL1. In conclusion, DHA inhibits poly (I:C)- or TNF-α-induced cytokine expression and NF-κB activation by reducing intracellular and mitochondrial ROS in PSCs. Consumption of DHA-rich foods may be beneficial in preventing chronic pancreatitis by inhibiting cytokine expression in PSCs.