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Rapamycin and CCI‐779 inhibit the mammalian target of rapamycin signalling in hepatocellular carcinoma
Author(s) -
Hui Ivan ChunFai,
Tung Edmund KwokKwan,
Sze Karen ManFong,
Ching YickPang,
Ng Irene OiLin
Publication year - 2010
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2009.02117.x
Subject(s) - pi3k/akt/mtor pathway , cell growth , cancer research , cell cycle , sirolimus , apoptosis , rptor , hepatocellular carcinoma , sorafenib , cell culture , mechanistic target of rapamycin , cell , chemistry , biology , pharmacology , medicine , biochemistry , genetics
Background: The mammalian target of rapamycin (mTOR), which phosphorylates p70S6K and 4EBP1 and activates the protein translation process, is upregulated in cancers and its activation may be involved in cancer development. Aims: In this study, we investigated the tumour‐suppressive effects of rapamycin and its new analogue CCI‐779 on hepatocellular carcinoma (HCC). Methods: Rapamycin and its new analogue CCI‐779 were applied to treat HCC cells. Cell proliferation, cell cycle profile and tumorigenicity were analysed. Results: In human HCCs, we observed frequent (67%, 37/55) overexpression of mTOR transcripts using real‐time reverse transcriptase‐polymerase chain reaction. Upon drug treatment, PLC/PRF/5 showed the greatest reduction in cell proliferation using the colony formation assay, as compared with HepG2, Hep3B and HLE. Rapamycin was a more potent antiproliferative agent than CCI‐779 in HCC cell lines. Proliferation assays by cell counting showed that the IC 50 value of rapamycin was lower than that of CCI‐779 in PLC/PRF/5 cells. Furthermore, flow cytometric analysis showed that both drugs could arrest HCC cells in the G 1 phase but did not induce apoptosis of these cells, suggesting that these mTOR inhibitors are cytostatic rather than cytotoxic. Upon rapamycin and CCI‐779 treatment, the phosphorylation level of mTOR and p70S6K in HCC cell lines was significantly reduced, indicating that both drugs can suppress mTOR activity in HCC cells. In addition, both drugs significantly inhibited the growth of xenografts of PLC/PRF/5 cells in nude mice. Conclusions: Our findings indicate that rapamycin and its clinical analogue CCI‐779 possess tumour‐suppressive functions towards HCC cells.