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

Sung-Eun Hong; Eun-Kyu Kim; Hyeon-Ok Jin; Hyun-Ah Kim; Jin Kyung Lee; Jae Soo Koh; Hyesil Seol; Jong-Il Kim; In-Chul Park; Woo Chul Noh

doi:10.1007/s10565-013-9253-2

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

Cell Biol Toxicol. 2013 Aug;29(4):273-82. doi: 10.1007/s10565-013-9253-2. Epub 2013 Aug 15.

Authors

Sung-Eun Hong¹, Eun-Kyu Kim, Hyeon-Ok Jin, Hyun-Ah Kim, Jin Kyung Lee, Jae Soo Koh, Hyesil Seol, Jong-Il Kim, In-Chul Park, Woo Chul Noh

Affiliation

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. sungeun@kirams.re.kr

PMID: 23942996
DOI: 10.1007/s10565-013-9253-2

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects*
Breast Neoplasms / drug therapy
Cell Line, Tumor
Cell Survival / drug effects
Drug Resistance, Neoplasm / drug effects
Female
Gene Expression / drug effects
Humans
Imidazoles / pharmacology
Inhibitor of Apoptosis Proteins / biosynthesis
Inhibitor of Apoptosis Proteins / genetics
Inhibitor of Apoptosis Proteins / metabolism*
MCF-7 Cells
Myeloid Cell Leukemia Sequence 1 Protein / biosynthesis
Myeloid Cell Leukemia Sequence 1 Protein / genetics
Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
Piperazines / pharmacology
RNA Interference
RNA, Small Interfering
Receptors, Estrogen / drug effects
Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors*
Ribosomal Protein S6 Kinases, 70-kDa / genetics
Survivin
Tamoxifen / pharmacology*

Substances

BIRC5 protein, human
Imidazoles
Inhibitor of Apoptosis Proteins
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
PF-4708671
Piperazines
RNA, Small Interfering
Receptors, Estrogen
Survivin
Tamoxifen
Ribosomal Protein S6 Kinases, 70-kDa
ribosomal protein S6 kinase, 70kD, polypeptide 1