在EML4-ALK L1196M和EML4-ALK G1202R突变非小细胞肺癌细胞中,SIRT1沉默通过AMPK/mTOR/S6K信号通路调节自噬,从而促进EMT和克唑替尼耐药。

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-11-01 Epub Date: 2024-07-30 DOI:10.1002/mc.23799
Qian Yang, Keyan Sun, Tianyu Gao, Ying Gao, Yuying Yang, Zengqiang Li, Daiying Zuo
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引用次数: 0

摘要

大多数EML4-ALK重排非小细胞肺癌(NSCLC)患者在接受治疗后不可避免地会产生获得性耐药性。耐药的主要机制是 ALK 激酶域的获得性二次突变。L1196M和G1202R是典型的突变位点。我们迫切需要了解耐药的潜在分子机制,以研究突变耐药NSCLC细胞的治疗靶点。沉默信息调节因子sirtuin1(SIRT1)能调节细胞的正常能量代谢,但其在癌症中的作用尚不清楚。在我们的报告中发现,与EML4-ALK NSCLC细胞相比,EML4-ALK G1202R和EML4-ALK L1196M突变耐药细胞中的SIRT1被下调。SIRT1的高表达与肺癌患者更长的生存时间有关。激活 SIRT1 能诱导自噬,抑制突变细胞的侵袭和迁移。进一步的实验表明,SIRT1 的激活通过上调 AMPK 的表达来抑制 mTOR 和 S6K 的磷酸化水平,从而激活自噬。SIRT1 能显著增强突变细胞对克唑替尼的敏感性,提高其促进突变细胞凋亡的能力,并抑制细胞增殖。总之,SIRT1是EML4-ALK L1196M和G1202R突变细胞耐药性的关键调控因子。SIRT1可能是EML4-ALK耐药NSCLC的一个新的治疗靶点。
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SIRT1 silencing promotes EMT and Crizotinib resistance by regulating autophagy through AMPK/mTOR/S6K signaling pathway in EML4-ALK L1196M and EML4-ALK G1202R mutant non-small cell lung cancer cells.

Most EML4-ALK rearrangement non-small cell lung cancer (NSCLC) patients inevitably develop acquired drug resistance after treatment. The main mechanism of drug resistance is the acquired secondary mutation of ALK kinase domain. L1196M and G1202R are classical mutation sites. We urgently need to understand the underlying molecular mechanism of drug resistance to study the therapeutic targets of mutant drug-resistant NSCLC cells. The silent information regulator sirtuin1 (SIRT1) can regulate the normal energy metabolism of cells, but its role in cancer is still unclear. In our report, it was found that the SIRT1 in EML4-ALK G1202R and EML4-ALK L1196M mutant drug-resistant cells was downregulated compared with EML4-ALK NSCLC cells. The high expression of SIRT1 was related to the longer survival time of patients with lung cancer. Activation of SIRT1 induced autophagy and suppressed the invasion and migration of mutant cells. Further experiments indicated that the activation of SIRT1 inhibited the phosphorylation level of mTOR and S6K by upregulating the expression of AMPK, thus activating autophagy. SIRT1 can significantly enhanced the sensitivity of mutant cells to crizotinib, improved its ability to promote apoptosis of mutant cells, and inhibited cell proliferation. In conclusion, SIRT1 is a key regulator of drug resistant in EML4-ALK L1196M and G1202R mutant cells. SIRT1 may be a novel therapeutic target for EML4-ALK drug resistant NSCLC.

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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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