S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin

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• 作者：Sung-Eun Hong (1) (5)
  Eun-Kyu Kim (2)
  Hyeon-Ok Jin (1)
  Hyun-Ah Kim (2)
  Jin Kyung Lee (3)
  Jae Soo Koh (4)
  Hyesil Seol (4)
  Jong-Il Kim (5)
  In-Chul Park (1)
  Woo Chul Noh (2)
  
• 关键词：Endocrine therapy resistance ; Mammalian target of rapamycin ; PF4708671 ; S6 kinase 1 ; Tamoxifen
• 刊名：Cell Biology and Toxicology
• 出版年：2013
• 出版时间：August 2013
• 年：2013
• 卷：29
• 期：4
• 页码：273-282
• 全文大小：345KB
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• 作者单位：Sung-Eun Hong (1) (5)
  Eun-Kyu Kim (2)
  Hyeon-Ok Jin (1)
  Hyun-Ah Kim (2)
  Jin Kyung Lee (3)
  Jae Soo Koh (4)
  Hyesil Seol (4)
  Jong-Il Kim (5)
  In-Chul Park (1)
  Woo Chul Noh (2)
  
  1. Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, 139-706, Republic of Korea
  5. Department of Food and Microbial Technology, Seoul Women’s University, 126 Gongneung-dong, Nowon-gu, Seoul, 139-774, Republic of Korea
  2. Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, 139-706, Republic of Korea
  3. Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, 139-709, Republic of Korea
  4. Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, 139-706, Republic of Korea
  

文摘

S6 kinase 1 (S6K1) was suggested to be a marker for endocrine therapy resistance in breast cancer. We examined whether tamoxifen’s effect can be modulated by S6K1 inhibition. S6K1 inhibition by PF4708671, a selective inhibitor of S6K1, acts synergistically with tamoxifen in S6K1-high MCF-7 cells. Similarly, the knockdown of S6K1 with small interfering RNA (siRNA) significantly sensitized MCF-7 cells to tamoxifen. Inhibition of S6K1 by PF4708671 led to a marked decrease in the expression levels of the anti-apoptotic proteins Mcl-1 and survivin, which was not related to mRNA levels. In addition, suppression of Mcl-1 or survivin, using specific siRNA, further enhanced cell sensitivity to tamoxifen. These results showed that inhibition of S6K1 acts synergistically with tamoxifen, via translational modulation of Mcl-1 and survivin. Based on these findings, we propose that targeting S6K1 may be an effective strategy to overcome tamoxifen resistance in breast cancer.