{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kadera BE"],"funding":["NIDDK NIH HHS","NCI NIH HHS"],"pagination":["157-65"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4286535"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["21(1)"],"pubmed_abstract":["<h4>Purpose</h4>Expression of CBL, an ubiquitin ligase, is decreased in 60% of human pancreatic ductal adenocarcinomas (PDAC) and is associated with shorter overall survival. We sought to determine how low CBL directly contributes to clinically more aggressive PDAC.<h4>Experimental design</h4>Human PDACs were stained for CBL, pEGFR, and EGFR. CBL-low was modeled in PDAC cells (Panc-1, L3.6pl, and AsPC-1) via transient transfection (siRNA) or stable knockdown (shRNA). Cell viability and apoptosis were measured by MTT assays and FACS. Immunoblot and a phospho-receptor tyrosine kinase (pRTK) array were used to probe signal transduction. NOD-scid-IL2Rγ(null) mice were subcutaneously implanted with PDAC or PDAC(CBL-low) cells on opposite flanks and treated with gemcitabine ± erlotinib for ≥4 weeks.<h4>Results</h4>There was an inverse correlation between CBL and pEGFR protein expression in 12 of 15 tumors. CBL knockdown increased PDAC resistance to gemcitabine and 5-fluorouracil (5-FU) by upregulating pEGFR (Y1068), pERK, and pAKT. A pRTK array of PDAC(CBL-low) cells revealed additional activated tyrosine kinases but all to a much lower magnitude than EGFR. Increased chemoresistance from low CBL was abrogated by the EGFR inhibitor erlotinib both in vitro and in vivo. Erlotinib+gemcitabine-treated PDAC(CBL-low) cells exhibited greater apoptosis by cleaved PARP, caspase-3, and Annexin V/PI.<h4>Conclusions</h4>Low CBL causes chemoresistance in PDAC via stress-induced EGFR activation that can be effectively abrogated by EGFR inhibition. These results suggest that dysregulation of ubiquitination is a key mechanism of EGFR hyperactivation in PDAC and that low CBL may define PDAC tumors likely to respond to erlotinib treatment."],"journal":["Clinical cancer research : an official journal of the American Association for Cancer Research"],"pubmed_title":["Low expression of the E3 ubiquitin ligase CBL confers chemoresistance in human pancreatic cancer and is targeted by epidermal growth factor receptor inhibition."],"pmcid":["PMC4286535"],"funding_grant_id":["P30 DK041301","P30 DK41301","R01 CA187678","T32 DK007180"],"pubmed_authors":["Wu N","Kadera BE","Donahue TR","Nguyen AH","Dawson DW","Toste PA","Li L"],"additional_accession":[]},"is_claimable":false,"name":"Low expression of the E3 ubiquitin ligase CBL confers chemoresistance in human pancreatic cancer and is targeted by epidermal growth factor receptor inhibition.","description":"<h4>Purpose</h4>Expression of CBL, an ubiquitin ligase, is decreased in 60% of human pancreatic ductal adenocarcinomas (PDAC) and is associated with shorter overall survival. We sought to determine how low CBL directly contributes to clinically more aggressive PDAC.<h4>Experimental design</h4>Human PDACs were stained for CBL, pEGFR, and EGFR. CBL-low was modeled in PDAC cells (Panc-1, L3.6pl, and AsPC-1) via transient transfection (siRNA) or stable knockdown (shRNA). Cell viability and apoptosis were measured by MTT assays and FACS. Immunoblot and a phospho-receptor tyrosine kinase (pRTK) array were used to probe signal transduction. NOD-scid-IL2Rγ(null) mice were subcutaneously implanted with PDAC or PDAC(CBL-low) cells on opposite flanks and treated with gemcitabine ± erlotinib for ≥4 weeks.<h4>Results</h4>There was an inverse correlation between CBL and pEGFR protein expression in 12 of 15 tumors. CBL knockdown increased PDAC resistance to gemcitabine and 5-fluorouracil (5-FU) by upregulating pEGFR (Y1068), pERK, and pAKT. A pRTK array of PDAC(CBL-low) cells revealed additional activated tyrosine kinases but all to a much lower magnitude than EGFR. Increased chemoresistance from low CBL was abrogated by the EGFR inhibitor erlotinib both in vitro and in vivo. Erlotinib+gemcitabine-treated PDAC(CBL-low) cells exhibited greater apoptosis by cleaved PARP, caspase-3, and Annexin V/PI.<h4>Conclusions</h4>Low CBL causes chemoresistance in PDAC via stress-induced EGFR activation that can be effectively abrogated by EGFR inhibition. These results suggest that dysregulation of ubiquitination is a key mechanism of EGFR hyperactivation in PDAC and that low CBL may define PDAC tumors likely to respond to erlotinib treatment.","dates":{"release":"2015-01-01T00:00:00Z","publication":"2015 Jan","modification":"2026-04-29T11:15:34.146Z","creation":"2019-03-27T01:42:54Z"},"accession":"S-EPMC4286535","cross_references":{"pubmed":["25348515"],"doi":["10.1158/1078-0432.CCR-14-0610","10.1158/1078-0432.ccr-14-0610"]}}