Abstract
Pancreatic cancer is lethal because of its invasiveness, rapid progression, and profound resistance to chemotherapy and radiation therapy. To identify the molecular mechanisms underlying this, we have examined the expression and potency of three major death receptors: tumor necrosis factor receptor (TNF-R), TNF-related apoptosis-inducing ligand receptor (TRAIL-R), and Fas in mediating cytotoxicity in four invasive pancreatic cancer cell lines. We have analyzed the expression of major antiapoptotic factors, cell cycle regulators and death receptor decoys (DcR) in comparison with normal pancreas tissues and five other human malignant tumor cell lines. We have found that different pancreatic cancer cell lines coexpress high-level TRAIL-R, Fas, and TNF-R1 but are strongly resistant to apoptosis triggered by the death receptors. DcR2 and DcR3 overexpression may partly contribute to the resistance of pancreatic cancer cells to TRAIL-R- and Fas-mediated cytotoxicity. Bcl-XL and Bcl-2 are predominantly overexpressed in pancreatic cancer cell lines, respectively. Bcl-XL is also predominantly overexpressed in prostate, colorectal, and intestinal cancer cells. The knockdown of the predominant Bcl-XL overexpression significantly reduces the viability of pancreatic cancer cells to TNFalpha- and TRAIL-mediated apoptosis by sublethal-dose single and combined antitumor drugs, including geldanamycin, PS-341, Trichostatin A, and doxorubicine. Geldanamyin and PS-341 synergistically block NFkappaB activation, suppress Akt/PKB pathway, and down-regulate Bcl-XL, Bcl-2, cIAP-1, and cyclin D1 expression. This combined regimen dramatically enhances TRAIL cytotoxic effects and breaks through chemoresistance. Bcl-XL plays a vital role in pancreatic cancer chemoresistance. Geldanamycin, PS-341, and TRAIL triple combination may be a novel therapeutic strategy for pancreatic cancer.
Highlights
Pancreatic cancer is extraordinarily lethal because of its invasive growth, rapid progression, and profound resistance to any therapy offered [1]
Suicide program that is highly conserved among all species. This regulated cell death process is primarily mediated by three different types of death receptors: tumor necrosis factor receptor (TNF-R), TNF-related apoptosis-inducing ligand receptor (TRAIL-R), and Fas and plays a critical role in removing unwanted cells during embryogenesis, immune responses, and tissue homeostasis [4]
Which antiapoptotic factors are predominantly overexpressed? Do the predominantly overexpressed antiapoptotic factors play a vital role in chemoresistance? What roles may DcRs play in pancreatic cancer cell survival? To answer these questions, we have examined the surface expression of TNF-R1 and TRAIL-R1/2 and Fas in four pancreatic cancer cell lines with diverse biological characteristics and have analyzed their potency in mediating apoptosis
Summary
Pancreatic cancer is extraordinarily lethal because of its invasive growth, rapid progression, and profound resistance to any therapy offered [1]. Suicide program that is highly conserved among all species This regulated cell death process is primarily mediated by three different types of death receptors: tumor necrosis factor receptor (TNF-R), TNF-related apoptosis-inducing ligand receptor (TRAIL-R), and Fas and plays a critical role in removing unwanted cells during embryogenesis, immune responses, and tissue homeostasis [4]. These natural surveillance mechanisms against tumorigenesis are severely compromised in pancreatic cancer. Its role in pancreatic cancer chemoresistance has not been established
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