Abstract
TRAIL and agonistic death receptor-specific antibodies can induce apoptosis in cancer cells with little cytotoxicity to normal cells. To improve TRAIL-induced antitumor effects, we tested its effectiveness in combination with pifithrin (PFT)-μ, which has the potential to inhibit HSP70 function and autophagy, both of which participate in TRAIL resistance in cancer cells. Among the four human pancreatic cancer cell lines tested, MiaPaca-2, Panc-1, and BxPC-3 cells showed varying sensitivities to TRAIL. In MiaPaca-2 and Panc-1 cells, knockdown of HSP70 or beclin-1, the latter an autophagy-related molecule, by RNA interference augmented TRAIL-induced antitumor effects, decreasing cell viability, and increasing apoptosis. On the basis of these findings, we next determined whether the TRAIL-induced antitumor effects could be augmented by its combination with PFT-μ. The combination of TRAIL plus PFT-μ significantly decreased the viability and colony-forming ability of MiaPaca-2 and Panc-1 cells compared with cells treated with either agent alone. When applied alone, PFT-μ increased Annexin V(+) cells in both caspase-dependent and -independent manners. It also promoted TRAIL-induced apoptosis and arrested cancer cell growth. Furthermore, PFT-μ antagonized TRAIL-associated NF-κB activation in cancer cells. In a xenograft mouse model, combination therapy significantly inhibited MiaPaca-2 tumor growth compared with treatment with either agent alone. The results of this study suggest protective roles for HSP70 and autophagy in TRAIL resistance in pancreatic cancer cells and suggest that PFT-μ is a promising agent for use in therapies intended to enhance the antitumor effects of TRAIL.
Highlights
Members of the TNF cytokine family, such as TNF-a and the Fas ligand, play important roles in inflammation and immunity [1]
We investigated the possibility that PFT-m, a smallmolecule HSP70 inhibitor that has the ability to alter autophagy [24], could enhance TRAIL-induced antitumor effects on human pancreatic cancer cells
We found that both HSP70 and autophagy are, at least in part, responsible for the TRAIL resistance of cancer cells and that PFTm enhances TRAIL-induced antitumor effects on human pancreatic cancer cells
Summary
Members of the TNF cytokine family, such as TNF-a and the Fas ligand, play important roles in inflammation and immunity [1]. Their use in anticancer therapy is limited because they cause severe cytotoxicity to normal cells. TRAIL, a member of the TNF superfamily, can induce apoptosis in cancer cells while causing almost no cytotoxicity to normal cells [2]. TRAIL binds to death receptors (DR) and activates caspases, leading to apoptosis. The binding of TRAIL to death receptors activates NF-kB, PKC, mitogen-activated protein kinase (MAPK), and AKT signaling [6, 7], thereby promoting cell proliferation and apoptosis resis-
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