title: Nuclear EGFR impairs ASPP2-p53 complex-induced apoptosis by inducing SOS1 expression in hepatocellular carcinoma.
abstract: ASPP2 can bind to p53 and enhance the apoptotic capabilities of p53 by guiding it to the promoters of pro-apoptotic genes. Here, ASPP2 overexpression for 24 hours transiently induced apoptosis in hepatoma cells by enhancing the transactivation of p53 on pro-apoptotic gene promoters. However, long-term ASPP2 overexpression (more than 48 hours) failed to induce apoptosis because p53 was released from the pro-apoptotic gene promoters. In non-apoptotic cells, nuclear EGFR induced SOS1 expression by directly binding to the SOS1 promoter. SOS1 activated the HRAS/PI3K/AKT pathway and resulted in nuclear translocation of p-AKT and Bcl-2. The interaction between p-AKT and ASPP2 facilitates Bcl-2 binding to p53, which releases p53 from the pro-apoptotic gene promoters. The in vivo assay demonstrated that EGFR/SOS1-promoted growth of nuclear p-AKT+, Bcl-2+ cells results in the resistance of hepatoma cells to ASPP2-p53 complex-induced apoptosis and that blocking nuclear translocation of EGFR dramatically improves and enhances the pro-apoptotic function of ASPP2. Finally, the activation of the HRAS/PI3K/AKT pathway by EGFR-induced SOS1 also inhibits cisplatin-induced apoptosis, suggesting a common apoptosis-evasion mechanism in hepatoma cells. Because evasion of apoptosis contributes to treatment resistance in hepatoma, our results also support further investigation of combined therapeutic blockade of EGFR and SOS1.
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.|Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.|Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Yabo
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.|Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.
authors.forename: Shichun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.|Beijing Institute of Hepatology, Beijing, 100069, China.
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D020837:SOS1 Protein / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D020837:SOS1 Protein; C495901:TP53 protein, human; C090468:TP53BP2 protein, human; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin
keywords: ASPP2; EGFR; SOS1; apoptosis; p53