PROX1, a Key Mediator of the Anti-Proliferative Effect of Rapamycin on Hepatocellular Carcinoma Cells

Cells

Kiwon Ban¹  Jung-Suk Sung²  Sora Kwon³  Inho Choi³  Young-Kwon Hong⁴ 

[1] Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China;Department of Life Science, Dongguk University, Goyang 10326, Korea;Department of Pharmaceutical Engineering, Hoseo University, Asan 31499, Korea;Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Soutern California, Los Angeles, CA 90033, USA;

关键词: hepatocellular carcinoma;    MTOR;    rapamycin;    PROX1;    antiproliferation;   

DOI  :  10.3390/cells11030446

来源: DOAJ

【 摘 要 】

The MTOR signal is known to be activated in various cancer cells including hepatocellular carcinoma (HCC) cells. Rapamycin, a specific inhibitor of MTOR, has been widely used as an immunosuppressant in organ transplant patients, and its clinical application has been recently expanded to cancer therapy. In this study, the anti-proliferative effect of rapamycin was investigated in four different HCC cell lines. Rapamycin effectively inhibited the proliferation of Huh7 or Hep3B, but not that of HepG2 or SNU3160 cells. Interestingly, rapamycin increased Prospero-related homeobox 1 (PROX1) expression at the protein level, but did not affect its transcript in Huh7 as well as Hep3B cells. Moreover, immunoprecipitation assays showed that PROX1 ubiquitination was downregulated by rapamycin. Furthermore, PROX1 over-expression or siRNA knock-down in Huh7 and Hep3B cells reduced or increased proliferation, respectively. The effect of PROX1 over-expression on the sensitivity to rapamycin was not synergistic, but the effect of MTOR inhibition on cell proliferation was diminished by PROX1 siRNA. Finally, Huh7 cells were inoculated into the flanks of nude mice and rapamycin was injected daily for 14 days. The xenograft volume was decreased and PROX1 expression was increased by rapamycin. These results indicate that PROX1 plays a key role in the anti-proliferative effect of rapamycin and suggest that the increased PROX1 by MTOR inhibition can be used as a useful marker for predicting whether HCC cells can be affected by rapamycin.

【 授权许可】

Unknown