title: RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer.
abstract: OBJECTIVE
  Pancreatic 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.
  
  
  METHODS
  Cell 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.
  
  
  RESULTS
  Our 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
  RLIP76 represents a mechanistically significant target for developing effective interventions in aggressive and refractory pancreatic cancers.
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Leake
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singhal
authors.forename: Lokesh Dalasanur
authors.initials: LD
authors.lastname: Nagaprashantha
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D059248:Chemoradiotherapy; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D017211:Treatment Failure
chemical_list: D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; C490620:Ralbp1 protein, mouse; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt