mTOR and P70 S6 Kinase Expression in Primary Liver Neoplasms

Abstract

Purpose: mTOR and P70 S6 kinase (S6K) play a key role in regulating protein translation. The role of mTOR and S6K in hepatocellular carcinoma has not been investigated, but this pathway is of particular interest because an effective inhibitor, rapamycin, is available. This study was undertaken to determine the prevalence and clinicopathological correlates of mTOR pathway activation in hepatocellular carcinoma and to determine whether rapamycin inhibits the pathway in cell culture.Experimental Design: Total and phosphorylated mTOR and S6K protein expression were studied by immunohistochemistry in hepatocellular carcinomas (n ‫؍‬ 73), fibrolamellar carcinomas (n ‫؍‬ 13), and hepatic adenomas (n ‫؍‬ 15). Results were correlated with tumor growth pattern as defined by the WHO (trabecular, pseudoglandular/acinar, compact, and scirrhous), tumor size, Ki-67 proliferation index, and the modified Edmondson nuclear grade, which has a scale of 1 to 4. HepG2 and Hep3B cell lines were treated with rapamycin to see the effect on proliferation and S6K phosphorylation.Results: Increased expression of total mTOR was seen in 5% of hepatocellular carcinoma, whereas overexpression of phospho-mTOR was evident in 15% of hepatocellular carcinoma. Phospho-mTOR positivity correlated with increased expression of total S6K, which was found in 45% of cases. Total S6K overexpression was positively correlated with tumor nuclear grade, inversely with tumor size, and was unassociated with the proliferation index or WHO growth pattern. Rapamycin treatment of HepG2 and Hep3B cell lines markedly inhibited cell proliferation and reduced S6K phosphorylation in both cell lines.Conclusions: The mTOR pathway is activated in a subset of hepatocellular carcinoma. Rapamycin can inhibit proliferation of neoplastic hepatocytes in cell culture.

AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma

“…High tumor proliferation induced by ERK activation is closely linked to chemotherapy resistance (28). Because the blockage of a MEK/ERK pathway can be overcome by other molecular abnormalities, including Janus-activated kinase/signal transducers and activators of transcription (22), focal adhesion kinase (41), and the mammalian target of rapamycin (42), it is likely that HCC could develop resistance to MEK inhibitors. The clinical effectiveness of inhibitors of the MEK/ERK pathway may be limited when administered alone, as HCC tumors possess more than one genetic defect (43).…”

Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells

“…Activation of p70S6K and dysregulation of eIF4E have been observed in many tumors and cancer cells, [29][30][31] and overexpression of both eIF4E and 4EBP1 in gastrointestinal carcinomas has been reported. 32 However, we found that AFPGC cells were different from CGC cells in that cisplatin minimally affected the phosphorylation of p70S6K and 4EBP1.…”

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc Δ716 mice

“…S3 A-D). Increased expression of mTOR protein has been reported for several types of human tumors, including colon cancer (22,23), and reduced expression of mTOR protein impairs the mTORC1 signaling (2).…”