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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.

SUBMITTER: Wang YL

PROVIDER: S-EPMC3648559 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Akt1 enhances CA916798 expression through mTOR pathway.

Wang Yu-Liang YL Zhu Bing-Jing BJ Qi Zhan-Zhong ZZ Wang Hai-Jing HJ Zhou Xiang-Dong XD

PloS one 20130508 5

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 posi ...[more]

PMID: 23667466

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Project description:Osteosarcoma (OS) is a primary malignant tumor that occurs in bone, and mainly affects children and adolescents. C?type lectin domain family 3 member A (CLEC3A) is a member of the C?type lectin superfamily, which regulates various biological functions of cells. The present study aimed to identify the effects and related mechanisms of CLEC3A in the proliferation and chemosensitivity of OS cells. The expression of CLEC3A in OS was analyzed using the Gene Expression Omnibus data profile GSE99671, and its expression in OS samples was verified using reverse transcription?quantitative PCR (RT?qPCR) and immunohistochemical staining. The relationship between the expression of CLEC3A and clinical traits in patients with OS was also analyzed, including age, tumor size, TNM stage and lymph node metastasis. Cell Counting Kit?8 assays, colony formation assays and cell cycle distribution analysis were used to determine the roles of CLEC3A in the proliferation and chemosensitivity of OS cells. Finally, RT?qPCR and western blotting were used to demonstrate the relationship between CLEC3A and the AKT1/mTOR/hypoxia?inducible factor 1?? (HIF1?) pathway. Both the mRNA and protein expression levels of CLEC3A were increased in OS tissues compared with adjacent non?tumor tissues, and this was positively associated with TNM stage and lymph node metastasis. The genetic knockdown of CLEC3A with small interfering RNA decreased OS cell proliferation and colony formation, and induced G1 phase arrest, whereas the overexpression of CLEC3A increased OS cell proliferation and colony formation, and alleviated G1 phase arrest. The suppression of CLEC3A also promoted enhanced the chemosensitivity of OS cells to doxorubicin (DOX) and cisplatin (CDDP); it also inhibited the expression of AKT1, mTOR and HIF1?, further to the nuclear localization of HIF1?, and HIF1? target gene expression levels, including VEGF, GLUT1 and MCL1 were also decreased. Furthermore, treatment with the AKT activator SC79 blocked the inhibitory effects of CLEC3A silencing in OS cells. In conclusion, these findings suggested that CLEC3A may function as an oncogene in OS, and that the suppression of CLEC3A may inhibit OS cell proliferation and promote chemosensitivity through the AKT1/mTOR/HIF1? signaling pathway.

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Akt1 enhances CA916798 expression through mTOR pathway.

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Akt1 enhances CA916798 expression through mTOR pathway.

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