title: Akt1 enhances CA916798 expression through mTOR pathway.
abstract: Multi-drug resistance leads to the failure of chemotherapy for cancers. Our previous study showed that overexpression of CA916798 led to multi-drug resistance. However, the underlying mechanisms remain unknown. In the current study, we observed that the levels of phosphorylated AKT, phosphorylated mTOR and CA916798 all increased in the drug resistant human adenocarcinoma samples and paralleled with the change of drug resistance. The results of immunofluorescence and Co-IP indicated that the positive correlation of CA916798 expression with AKT1 activation might be associated with drug resistance of lung adenocarcinoma. Furthermore, AKT1 stimulated CA916798 expression through mTOR pathway in both A549 and A549/CDDP cell lines, which was also observed in the xenografted tumor in nude mice. The results showed that CA916798 located in the downstream of PI3K/AKT/mTOR pathway. Inhibition of PI3K by LY294002 could efficiently reduce CA916798 expression and tumor size in vivo as well. Additionally, LY294002 combined with rapamycin inhibited CA916798 expression and tumor size stronger than LY294002 alone. Our findings may also provide a new explanation for synergistic anti-tumor effects of PI3K and mTORC1 inhibitors.
authors.affiliation: Department of Respiratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Wang
authors.forename: Bing-Jing
authors.initials: BJ
authors.lastname: Zhu
authors.forename: Zhan-Zhong
authors.initials: ZZ
authors.lastname: Qi
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Wang
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Zhou
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002867:Chromones; D017931:DNA Primers; D009025:Morpholines; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one