Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignant cancers [1] and the third leading cause of cancer-related deaths worldwide [2]
In an in vivo study using Huh7 xenograft, rapamycin reduced xenograft volume and increased Prospero-related homeobox 1 (PROX1) expression in tumors. These results indicate that PROX1 plays an important role in the anti-proliferative effect of rapamycin and suggest that PROX1 protein level might be a useful marker for anti-cancer therapy of rapamycin in HCC
Rapamycin significantly reduced the proliferation of Huh7 or Hep3B, but did not affect HepG2 or SNU3160 cells (Figure 1A), which suggests that rapamycin was not effective on all types of HCC
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignant cancers [1] and the third leading cause of cancer-related deaths worldwide [2]. Only 30% of HCC patients can be treated by liver resection, transplantation, or local ablation, mostly owing to its heterogeneous etiology. A small number of drugs are available to treat HCC patients [3]. Recent clinical trials have shown that sorafenib is not very effective for all HCC patients. Lenvatinib, a multikinase inhibitor, was approved for the treatment of advanced or unresectable HCC patients who had not received prior systemic therapy. OS proportions of patients treated with Lenvatinib were only 18%. It is highly required to identify molecular markers that predict the patients likely to benefit from sorafenib or lenvatinib chemotherapy [5,6]
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