Abstract
PurposePancreatic cancer is an aggressive malignancy with characteristic metastatic course of disease and resistance to conventional chemo-radiotherapy. RLIP76 is a multi-functional cell membrane protein that functions as a major mercapturic acid pathway transporter as well as key regulator of receptor-ligand complexes. In this regard, we investigated the significance of targeting RLIP76 on PI3K/Akt pathway and mechanisms regulating response to chemo-radiotherapy.Research Design and MethodsCell survival was assessed by MTT and colony forming assays. Cellular levels of proteins and phosphorylation was determined by Western blot analyses. The impact on apoptosis was determined by TUNEL assay. The anti-cancer effects of RLIP76 targeted interventions in vivo were determined using mice xenograft model of the pancreatic cancer. The regulation of doxorubicin transport and radiation sensitivity were determined by transport studies and colony forming assays, respectively.ResultsOur current studies reveal an encompassing model for the role of RLIP76 in regulating the levels of fundamental proteins like PI3K, Akt, E-cadherin, CDK4, Bcl2 and PCNA which are of specific importance in the signal transduction from critical upstream signaling cascades that determine the proliferation, apoptosis and differentiation of pancreatic cancer cells. RLIP76 depletion also caused marked and sustained regression of established human BxPC-3 pancreatic cancer tumors in nude mouse xenograft model. RLIP76 turned out to be a major regulator of drug transport along with contributing to the radiation resistance in pancreatic cancer.Conclusions/SignificanceRLIP76 represents a mechanistically significant target for developing effective interventions in aggressive and refractory pancreatic cancers.
Highlights
Pancreatic cancer is the fourth leading cause of cancer-related deaths among men and women [1]
Our current studies reveal an encompassing model for the role of RLIP76 in regulating the levels of fundamental proteins like PI3K, Akt, E-cadherin, cyclin dependent kinase 4 (CDK4), Bcl2 and PCNA which are of specific importance in the signal transduction from critical upstream signaling cascades that determine the proliferation, apoptosis and differentiation of pancreatic cancer cells
Following the characterization of enhanced expression of RLIP76, we further investigated the effect of RLIP76 inhibition or depletion in pancreatic cancer cells
Summary
Pancreatic cancer is the fourth leading cause of cancer-related deaths among men and women [1]. 80% to 90% are ductal adenocarcinomas [2,3]. PI3K/Akt signaling represents a potent and fundamental axis of signal relay that determines the basal survival and resistance to the apoptotic effects of chemo-radiotherapy in a variety of cancers, which makes PI3K/Akt pathway a central focus of mechanistic investigations in pancreatic cancer [13,14]. There is no effective treatment for pancreatic cancer and conventional chemo-radiotherapy has shown very limited success in improving patient survival. The investigation of the mechanisms of action of novel targets which can regulate the molecular changes that drive the pancreatic cancer survival and refractoriness to therapy will facilitate the development of effective interventions for pancreatic cancer [4,15]
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