Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma.
Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma.
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DOI：
10.18632/oncotarget.10161
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Ono M
中科院分区：
文献类型：
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作者：
Watari K;Nishitani A;Shibata T;Noda M;Kawahara A;Akiba J;Murakami Y;Yano H;Kuwano M;Ono M
肝细胞癌（HCC）是世界范围内最常见的癌症之一。虽然最近的研究促进了关键基因和相关调控途径的鉴定，但针对晚期HCC的治疗方法仍不够有效。因此，我们的目标是开发有效的治疗方法，为HCC患者的治疗效果提供可靠的生物标志物。为此，我们首先比较了各种抗癌药物在从单个HCC肿瘤建立的分化良好（HAK-1A）和分化不良（HAK-1B）细胞系之间的细胞毒性作用。在筛选的各种药物中，HAK-1B细胞对mTORC 1抑制剂（雷帕霉素类似物）、雷帕霉素和依维莫司的敏感性比HAK-1A细胞高2,000倍。尽管雷帕霉素类似物抑制HAK-1A和HAK-1B细胞中mTOR Ser 2448的磷酸化，但仅在HAK-1B细胞中特异性抑制mTOR Ser 2481的磷酸化。Raptor基因的沉默仅能诱导HAK-1B细胞凋亡并抑制其生长。此外，独立于三名HCC患者的肿瘤建立的其他三种细胞系对雷帕霉素的敏感性也高出约2,000倍，这与雷帕霉素对mTOR Ser 2481磷酸化的抑制密切相关。依维莫司治疗显著抑制低分化HAK-1B和KYN-2细胞诱导的肿瘤生长和体内mTOR Ser 2481磷酸化。据我们所知，这是第一项研究表明，在mTORC 1成瘾的HCC细胞中，mTOR Ser 2481的磷酸化被雷帕霉素类似物选择性抑制，并且可能是雷帕霉素类似物治疗HCC患者的治疗效果的潜在可靠生物标志物。
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.