ROLE AND REGULATION OF S6 KINASE IN BREAST CANCER

Date

2013-04-12

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Sridharan, Savitha

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Purpose: The 40S ribosomal protein S6 kinase (S6K) acts downstream of the mammalian target of rapamycin (mTOR), which is an important target for cancer therapy. mTOR inhibitors are, however, of limited success, partly due to the activation of the oncogene Akt caused by persistent inhibition of p70 S6 kinase or S6K1 via a negative feedback loop. S6K exists as two homologs, S6K1 and S6K2. While both homologs are overexpressed in breast cancer, little is known about the regulation and functions of S6K2. The objective of the present study is to determine pathways promoting S6K overexpression and whether S6K homologs perform redundant or distinct functions with respect to Akt activation and breast cancer cell survival. Methods: Breast cancer cells were transfected with non-targeting siRNA or siRNA against appropriate proteins and treated with cell death stimuli such as tumor necrosis factor-alpha (TNF), TNF-related apoptosis-inducing ligand (TRAIL), doxorubicin and paclitaxel. Cell death was monitored by staining cells with Annexin V/Yo-pro and propidium iodide. The levels of various proteins were determined by Western blotting. Results: S6K levels correlated with hormone receptor status and signaling through the hormone receptor pathway increased S6K levels. Silencing of S6K1 inhibited whereas knockdown of S6K2 potentiated cell death by various apoptotic stimuli, including TNF and TRAIL. In contrast to S6K1, depletion of S6K2 decreased basal and TNF-induced Akt phosphorylation. Ectopic expression of constitutively-active Akt in MCF-7 cells restored cell survival in S6K2-depleted cells. We have previously shown that activation of Akt induces downregulation of Bid via p53. Knockdown of S6K2 caused an increase in p53 and silencing of Bid blunted the ability of S6K2 deficiency to enhance TNF-induced apoptosis. Conclusions: Our study addresses the mechanism of S6K overexpression and demonstrates for the first time that the two homologs of S6K have distinct effects on Akt activation and cell survival. Thus, targeting S6K2 rather than mTOR may be an effective therapeutic strategy to treat cancers.

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