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Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma.

ABSTRACT: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy.RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated.p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not.In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.

SUBMITTER: Kim J

PROVIDER: S-EPMC3030253 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma.

Kim Jinhee J Jonasch Eric E Alexander Angela A Short John D JD Cai Shengli S Wen Sijin S Tsavachidou Dimitra D Tamboli Pheroze P Czerniak Bogdan A BA Do Kim Anh KA Wu Kevin J KJ Marlow Laura A LA Wood Christopher G CG Copland John A JA Walker Cheryl Lyn CL

Clinical cancer research : an official journal of the American Association for Cancer Research 20090101 1

<h4>Purpose</h4>p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy.<h4>Experimental design</h4>RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatid ...[more]

PMID: 19118035

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Project description:BackgroundHigh immunogenicity is an important feature of ccRCC, but its underlying immune-related molecular mechanisms remain unclear. This study aimed to investigate the effect of immune-related gene TEK on ccRCC and its prognostic value.MethodsThe immune-related differentially expressed genes (DEGs) and transcription factors (TFs) in ccRCC were screened based on The Cancer Genome Atlas (TCGA) database, and a regulatory network of TF was constructed. Prognostic-related immune genes were screened by univariate Cox regression analysis and functional annotation was performed. Univariate and multivariate Cox regression analyses were performed to construct the immune gene risk model and identify the hub gene TEK that independently affected the prognosis of ccRCC. The effectiveness of the TEK was verified by external microarray datasets. The relationship between TEK and immune cells in ccRCC was evaluated based on Tumor Immune Estimation Resource (TIMER). The expression of TEK in clinical specimens was verified by qRT-PCR and immunohistochemical (IHC) staining. MTT and cloning formation assay were used to evaluate cell proliferation. Transwell assays were used to assess cell migration. Apoptosis was assessed by flow cytometry, and the expression of related proteins was detected by Western blot and immunofluorescence.ResultsWe constructed a prognostic model consisting of 12 hub genes and performed risk scores to determine the relationship between these scores and prognosis. Through Cox regression analysis and survival analysis, TEK, an immune marker highly related to survival prognosis, was obtained and validated. In vitro experiments showed that knockdown of TEK promoted the proliferation and migration of ccRCC cells, and we found that TEK promoted apoptosis by regulating the phosphorylation of AKT, thereby inhibiting cell proliferation.ConclusionsTEK plays an important role in risk assessment and survival prediction for ccRCC patients as a new immune gene and maybe an emerging target for immunotherapy for ccRCC patients.

Dataset Information

Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma.

Publications

Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma.

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