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Sirt5调控k-ras野生型大肠癌耐药的机制研究
中文摘要

肿瘤细胞对细胞毒性药物的耐药是成功治疗大肠癌(colorectal cancer,CRC)病人的一大障碍。最近有研究认为在癌症治疗中,耐药与肿瘤代谢失调有关。sirtuin蛋白(Sirtl-7)是烟酰胺腺嘌呤二核苷酸(NAD+)依赖性去乙酰化酶,Sirt5是sirtuin蛋白家族的重要成员之一,主要存在于线粒体,但细胞浆和细胞核中也存在功能性的Sirt5蛋白。Sirt5最初被描述为赖氨酸去乙酰化酶,但其去乙酰化酶活性非常弱。Sirt5可以有效去除其目的蛋白赖氨酸残基的酸性酰基:琥珀酰基、丙二酰基和戊二酰基,从而影响不同的代谢通路中的酶。 最近,Lu等人发现Sirt5在晚期非小细胞肺癌(NSCLC)和小细胞肺癌中高表达,并且敲除Sirt5导致Nrf2水平降低。Nrf2在各种恶性肿瘤中重新编排以适应代谢重编程并促进多种恶性肿瘤的耐药性,因此敲除Sirt5提高了NSCLC对细胞毒性药物的敏感性。 基于以上事实,我们猜测Sirt5在肿瘤耐药方面有决定性作用,但潜在的机制仍不清楚。因此本课题旨在探究Sirt5介导的CRC代谢重编程如何调控细胞对化疗和靶向治疗的耐药。 本研究提出了一种根据细胞的存活类型即以Sift5表达为特征的细胞导致野生型Kras CRC耐药的机制。野生型Kras CRC中的Sirt5+细胞对化疗药物或西妥昔单抗耐受。我们发现其具体机制为Sirt5去丙二酰化琥珀酸脱氢酶复合体亚基A (succinate dehydrogenase complex subnit A,SDHA),并使其失活,导致代谢产物琥珀酸的积累。琥珀酸结合并激活活性氧清除酶硫氧还蛋白还原酶2(TrxR2)使细胞对化疗耐药。另外,Sirt5+细胞的琥珀酸/αKG的比例增高,抑制αKG依赖性双加氧酶以维持西妥昔单抗耐药。我们的发现表明Sirt5抑制剂与化疗药物和/或西妥昔单抗联用可能为Kras野生型CRC患者提供治疗策略。

英文摘要

Drug resistance against tumor cytotoxic drugs is a major obstacle to successful treatment of colorectal cancer (CRC) patients. Recent studies have suggested that drug resistance is related to metabolic disorders in the treatment of cancer. The sirtuin protein (Sirt1-7) is nicotinamide adenine dinucleotide (NAD +)-dependent lysine deacetylase. Sirt5 is one of the important members of the sirtuin protein family and is mainly present in mitochondria, cytoplasm and nucleus. The functional Sirt5 protein is also present in the nucleus. Studies have shown that whether in the mitochondria or outside, Sirt5 is more likely to catalyze the removal of negatively charged modifying groups, preferentially acting as a wide regulator of succinylation, malonylation, and glutarylation, affecting enzymes function in different metabolic pathways. Recent studies have shown that Sirt5 protein is highly expressed in non-small cell lung cancer. Deletion of Sirt5 expression inhibits the growth of non-small cell lung cancer and makes tumor cells more sensitive to drugs. Another study also demonstrated the relationship between Sirt5 and non-small cell lung cancer: nuclear factor erythroid-2 related factor 2 (Nrf2) is important for promoting growth and drug-resistance related proteins in non-small cell lung cancer. Regulating transcription factors and decreasing the expression of Sirt5 protein will reduce the expression of NFR2, which will reduce the growth rate and drug resistance of non-small cell lung cancer. Based on these facts, we hypothesize that Sirt5 plays a decisive role in the resistance of tumors to cancer treatment, but the underlying mechanism remains unclear. Therefore, our research aims to explore how Sirt5-mediated reprogramming of CRC metabolism regulates resistance to chemotherapy and targeted therapies. We have determined that a cell characterized by Sirt5 expression based on the type of cell survival leads to a wild-type Kras CRC resistance mechanism. Sirt5+ cells in wild-type Kras CRC are resistant to chemotherapeutic drugs or cetuximab. We found that the specific mechanism is that Sirt5 demalonylase succinate dehydrogenase complex subnit A (SDHA) and inactivate it, resulting in the accumulation of metabolite succinate. Succinate binds to and activates the active oxygen scavenging enzyme thioredoxin reductase 2 (TrxR2) to confer chemotherapy resistance. In addition, the proportion of succinate/aKG in Sirt5+ cells increased, and αKG-dependent dioxygenase was inhibited to maintain cetuximab resistance. Our findings suggest that the use of Sirt5 inhibitors in combination with chemotherapeutic drugs and/or cetuximab may provide a treatment strategy for patients with Kras wild-type CRC.

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