Antitumor effects of low-dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF-1α-expressing gastric cancer cells.
Antitumor effects of low-dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF-1α-expressing gastric cancer cells.
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低剂量tipifarnib对表达HIF-1α的胃癌细胞中MTOR信号通路和活性氧的产生的抗肿瘤作用。
DOI：
10.1002/2211-5463.13154
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发表时间：
2021-05
期刊：
影响因子：
2.6
通讯作者：
Noshiro H
中科院分区：
文献类型：
--
作者：
Egawa N;Tanaka T;Matsufuji S;Yamada K;Ito K;Kitagawa H;Okuyama K;Kitajima Y;Noshiro H
法尼基转移酶抑制剂（FTIs）通过抑制Ras信号传导抑制几种恶性肿瘤的侵袭性。然而，用低剂量的FTI替法尼治疗细胞可抑制缺氧诱导因子- 1α (HIF - 1α)的表达，并在不抑制Ras通路的情况下产生抗肿瘤作用。尽管我们之前报道过胃癌（GC）中HIF‐1α表达升高与侵袭性表型相关，但FTIs对胃癌的抗肿瘤作用知之甚少。在这项研究中，我们检测了低剂量替法尼的抗肿瘤作用与胃癌细胞中HIF - 1α表达之间的关系。在常压条件下，HIF‐1α仅在MKN45和KATOIII细胞中表达。在HIF‐1α阳性细胞中观察到替法尼尼对HIF‐1α的抑制作用。低剂量替法尼在体内和体外均仅对HIF - 1α阳性细胞有抗肿瘤作用。此外，低剂量的替法尼灭活ras同源物富集于大脑(Rheb)/哺乳动物雷帕霉素（mTOR）信号靶点，并降低HIF‐1α‐阳性GC细胞内活性氧（ROS）水平。我们的研究结果表明，低剂量的替法尼的抗肿瘤作用至少部分是通过抑制Rheb法尼化和降低ROS水平来抑制mTOR信号和HIF - 1α的表达。这些发现表明，低剂量的替法尼可能能够发挥抗肿瘤作用，这种作用依赖于胃癌细胞中HIF‐1α的表达。蒂法尼可能有潜力成为一种新的治疗HIF‐1α‐表达的具有侵袭性表型的GC的药物。低剂量替法尼通过抑制哺乳动物雷帕霉素信号靶点和活性氧产生对胃癌（GC）细胞具有抗肿瘤作用。替法尼的作用取决于缺氧诱导因子- 1α (HIF - 1α)的表达状态。HIF‐1α表达与胃癌的肿瘤侵袭性相关。替法尼可能代表了一种新的治疗胃癌的药物，表现出侵袭性表型。
Farnesyltransferase inhibitors (FTIs) suppress tumor aggressiveness in several malignancies by inhibiting Ras signaling. However, treatment of cells with a low dose of the FTI tipifarnib suppresses the expression of hypoxia‐inducible factor‐1α (HIF‐1α) and results in antitumor effects without inhibiting the Ras pathway. Although we previously reported that elevated HIF‐1α expression is associated with an aggressive phenotype in gastric cancer (GC), little is known about the antitumor effects of FTIs on GC. In this study, we examined the relationship between the antitumor effects of low‐dose tipifarnib and HIF‐1α expression in GC cells. Under normoxic conditions, HIF‐1α was expressed only in MKN45 and KATOIII cells. The inhibitory effect of tipifarnib on HIF‐1α was observed in HIF‐1α‐positive cells. Low‐dose tipifarnib had antitumor effects only on HIF‐1α‐positive cells both in vitro and in vivo. Furthermore, low‐dose tipifarnib inactivated ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) signaling and decreased intracellular reactive oxygen species (ROS) levels in HIF‐1α‐positive GC cells. Our results that the antitumor effects of low‐dose tipifarnib are at least partially mediated through suppression of mTOR signaling and HIF‐1α expression via inhibition of Rheb farnesylation and reduction in ROS levels. These findings suggest that low‐dose tipifarnib may be capable of exerting an antitumor effect that is dependent on HIF‐1α expression in GC cells. Tipifarnib may have potential as a novel therapeutic agent for HIF‐1α‐expressing GC exhibiting an aggressive phenotype. Low‐dose tipifarnib has antitumor effects on gastric cancer (GC) cells via suppression of mammalian target of rapamycin signaling and reactive oxygen species production. The effects of tipifarnib depend on hypoxia‐inducible factor‐1α (HIF‐1α) expression status. HIF‐1α expression is associated with cancer aggressiveness in GC. Tipifarnib may represent a novel therapeutic agent for GC exhibiting an aggressive phenotype.
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影响因子：
2.7
作者：
Hiraki M;Kitajima Y;Kai K;Nakamura J;Hashiguchi K;Noshiro H;Miyazaki K
通讯作者：
Miyazaki K
影响因子：
6.2
作者：
Jabbour, Elias;Kantarjian, Hagop;Ravandi, Farhad;Garcia-Manero, Guillermo;Estrov, Zeev;Verstovsek, Srdan;O'Brien, Susan;Faderl, Stefan;Thomas, Deborah A.;Wright, John J.;Cortes, Jorge
通讯作者：
Cortes, Jorge
影响因子：
4.8
作者：
Koshikawa, Nobuko;Hayashi, Jun-Ichi;Takenaga, Keizo
通讯作者：
Takenaga, Keizo
影响因子：
45.3
作者：
Johnston, SRD;Hickish, T;Howes, A
通讯作者：
Howes, A
影响因子：
7.5
作者：
Albert, Verena;Hall, Michael N.
通讯作者：
Hall, Michael N.