SMILE upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells

Cancer Lett. 2014 Nov 28;354(2):390-7. doi: 10.1016/j.canlet.2014.09.001. Epub 2014 Sep 6.


Metformin, a diabetes drug, has been reported to inhibit the growth of prostate cancer cells. In this study, we investigated the effect and action mechanism of metformin on the function of androgen receptor (AR), a key molecule in the proliferation of prostate cancer cells. Metformin was found to reduce androgen-dependent cell growth and the expression of AR target genes by inhibiting AR function in prostate cancer cells such as LNCaP and C4-2 cells. Interestingly, metformin upregulated the protein level of small heterodimer partner-interacting leucine zipper (SMILE), a coregulator of nuclear receptors, and knockdown of SMILE expression with shRNA abolished the inhibitory effect of metformin on AR function. Further studies revealed that SMILE protein itself suppressed the transactivation of AR, and its ectopic expression resulted in the repressed expression of endogenous AR target genes, PSA and NKX3.1, in LNCaP cells. In addition, SMILE protein physically interacted with AR and competed with the AR coactivator SRC-1 to modulate AR transactivation. As expected, SMILE repressed androgen-dependent growth of LNCaP and C4-2 cells. Taken together, these results suggest that SMILE, which is induced by metformin, functions as a novel AR corepressor and may mediate the inhibitory effect of metformin on androgen-dependent growth of prostate cancer cells.

Keywords: Androgen receptor; Corepressor; Metformin; Prostate cancer cells; SMILE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / biosynthesis
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Male
  • Metformin / pharmacology*
  • Mice
  • Neoplasms, Hormone-Dependent / drug therapy
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Transcriptional Activation
  • Up-Regulation / drug effects


  • Basic-Leucine Zipper Transcription Factors
  • CREBZF protein, human
  • Receptors, Androgen
  • Metformin