Luteolin-regulated MicroRNA-301-3p Targets Caspase-8 and Modulates TRAIL Sensitivity in PANC-1 Cells

Abstract

Background/Aim: MicroRNAs (miRNAs) play regulatory roles in pancreatic ductal adenocarcinoma (PDAC). However, it is still required to identify the function of miRNA-301-3p in pancreatic cancer cells. Materials and Methods: Effects of luteolin on cell growth, TRAIL cytotoxicity, and miR-301-3p levels were evaluated. The role of miRNA-301-3p in regulating cell proliferation, target gene expression, and TRAIL cytotoxicity were studied. Results: The levels of miR-301-3p were down-regulated in PANC-1 cells exposed to luteolin, which inhibits the growth of PANC-1 cells and sensitizes cells to TRAIL. The knockdown of miR-301-3p attenuates cell proliferation and enhances TRAIL cytotoxicity. In addition, caspase-8 was directly targeted by miR-301-3p. Conclusion: Our findings unveil a critical biological function of miR-301-3p in regulating cell proliferation and elevating an antiproliferative effect of TRAIL on cancer cells. Our observation of miR-301-3p/caspase-8 relationship can also serve to clarify the role of miR-301-3p in other cancer types and related diseases.Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and a highly fatal malignancy with lymph node or distant metastases upon diagnosis. PDAC is predicted to be the second principal cause of cancer-related deaths by the year 2030 (1). Despite much progress on pancreatic cancer research over the past decades, surgery is the only attempt towards a curative outcome (2). Insufficient clinical efficacy of chemotherapy and radiation therapy has been reported and attributed to drug resistance in PDAC (3-6). Several signaling pathways, including nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) signaling, are activated, leading to cell growth and metastasis in PDAC. Mutations in tumor suppressor genes are also detected in PDAC (5, 7-9). A better understanding of the molecular characteristics of PDAC can lead to development of novel treatment strategies to combat PDAC.Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. TRAIL has been known to inhibit cell growth by inducing cell-cycle arrest (10,11). In addition, anticancer effects of TRAIL can occur through death receptors 4 and 5, which generally regulate the activation of caspases, a family of cysteine proteases (12-14). Upon TRAIL binding, activation of caspase-8 cleaves executioner caspases, such as caspase-3 and -7, by which effective caspases contribute to chromatin condensation and nuclear fragmentation with the formation of apoptotic bodies (12-15). Indeed, TRAIL-induced apoptosis is impeded by the low expression of death receptors and caspases (16-18). Moreover, TRAIL resistance is associated with FADD-like ICE inhibitory proteins (FLIP) and inhibitor of apoptosis (IAP) family, such as cIAP, XIAP, and survivin, which inhibit the activation of caspases (19). Accumulating evidence has shown that combination of TRAIL with cancer therapeutic agents is effective to subdue TRAIL resistance. For instance, trea...

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“…This reduced migration and invasion of A431-III cells and decreased metastasis in a xenograft zebrafish model [384]. Similarly, miRNA-301-3p was downregulated in pancreatic cancer cells following treatment with luteolin, causing a decrease in cell growth [380]. In several ovarian cancer cell lines, luteolin induced apoptosis through the extrinsic and intrinsic pathways.…”

“…Caused cell cycle arrest [362,[374][375][376][377]. Decreased cell viability and proliferation [378][379][380][381][382][383].…”

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“…Antrocin [119], benzyl isothiocyanate [120], capsaicin [121], curcumin [122], quercetin [123], genistein [124], ginsenoside [125], emodin [126], oleuropein [127], resveratrol [128], and other secondary metabolites that could affect the regulation of miRNAs' expression and their natural sources are shown in Table 1. Evidence-Based Complementary and Alternative Medicine Achillea millefolium (Asteraceae) [143] Evidence-Based Complementary and Alternative Medicine [154]. Also, Wang et al reported that the therapeutic potential of fish oil supplementation on cholesterol metabolic disorder and hepatic triglyceride is mediated through regulating the particular miRNAs' expression (rno-miR-33-5p and rno-miR-34a-5p) in Westernstyle diet-induced NAFLD rats [155].…”

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“…In pancreatic cancer cells, luteolin treatment is associated with down-regulation of miR-301-3p, which directly targets caspase-8, an initiator of the extrinsic apoptosis pathway. Also, luteolin treatment and knockdown of miR-301-3p sensitized pancreatic cancer cells to the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) ( Moeng et al, 2020 ). This is a potent apoptosis inducer of the TNF cytokine superfamily, which was also tested as a recombinant anti-cancer agent, but with reported high resistance rates after repeated treatments ( Wong et al, 2019 ).…”