Research Papers:

Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma

Kosuke Watari, Ayumi Nishitani, Tomohiro Shibata, Masaki Noda, Akihiko Kawahara, Jun Akiba, Yuichi Murakami, Hirohisa Yano, Michihiko Kuwano and Mayumi Ono _

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Oncotarget. 2016; 7:47403-47417. https://doi.org/10.18632/oncotarget.10161

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Kosuke Watari1,*, Ayumi Nishitani1,*, Tomohiro Shibata1, Masaki Noda1, Akihiko Kawahara2, Jun Akiba3, Yuichi Murakami1,4, Hirohisa Yano3, Michihiko Kuwano4, Mayumi Ono1

1Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

2Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan

3Department of Pathology, Kurume University School of Medicine, Kurume, Japan

4Cancer Translational Research Center, St. Mary’s Institute of Health Sciences, Kurume, Japan

*These authors contributed equally to this work

Correspondence to:

Mayumi Ono, email: [email protected]

Keywords: mTOR Ser2481, mTORC1, Raptor, rapalogs, hepatocellular carcinoma

Received: February 15, 2016     Accepted: June 07, 2016     Published: June 18, 2016


Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although recent studies facilitate the identification of crucial genes and relevant regulatory pathways, therapeutic approaches against advanced HCC are insufficiently effective. Therefore, we aimed here to develop potent therapeutics to provide a reliable biomarker for the therapeutic efficacy in patients with HCC. To this end, we first compared the cytotoxic effects of various anti-cancer drugs between well differentiated (HAK-1A) and poorly differentiated (HAK-1B) cell lines established from a single HCC tumor. Of various drug screened, HAK-1B cells were more sensitive by a factor of 2,000 to the mTORC1 inhibitors (rapalogs), rapamycin and everolimus, than HAK-1A cells. Although rapalogs inhibited phosphorylation of mTOR Ser2448 in HAK-1A and HAK-1B cells, phosphorylation of mTOR Ser2481 was specifically inhibited only in HAK-1B cells. Silencing of Raptor induced apoptosis and inhibited the growth of only HAK-1B cells. Further, three other cell lines established independently from the tumors of three patients with HCC were also approximately 2,000-fold times more sensitive to rapamycin, which correlated closely with the inhibition of mTOR Ser2481 phosphorylation by rapamycin. Treatment with everolimus markedly inhibited the growth of tumors induced by poorly differentiated HAK-1B and KYN-2 cells and phosphorylation of mTOR Ser2481 in vivo. To our knowledge, this is the first study showing that the phosphorylation of mTOR Ser2481 is selectively inhibited by rapalogs in mTORC1-addicted HCC cells and may be a potential reliable biomarker for the therapeutic efficacy of rapalogs for treating HCC patients.

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