Li Liangping, Huang Zetian, Huang Yuying, Li Yongkun, Ma Xuesong, Li Pingping, Du Wenqing, Wang Hui, Zhao Yufei, Zeng Shulan, Peng Yan, Zhang Guohai
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China; School of Pharmacy, Youjiang Medical University for Nationalities, Baise 533000, China.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
Bioorg Chem. 2024 Dec;153:107815. doi: 10.1016/j.bioorg.2024.107815. Epub 2024 Sep 11.
Immunomodulatory drugs (IMiDs) represented by thalidomide exhibit benefits when combined with other chemotherapeutic drugs for patients with lung cancer, which inspired the exploration of combining pomalidomide with another agent to treat lung cancer as it is more potent than thalidomide. However, the drugs that can be combined with pomalidomide to benefit patients and related mechanisms remain unclear. Here, we performed a proteomic analysis based on the streptavidin pull-down to identify the potential target of pomalidomide in non-small cell lung cancer (NSCLC). In this work, electron transfer flavoprotein alpha subunit (ETFA), an important enzyme involved in electron transport in the respiratory chains was identified as a crucial cellular target of pomalidomide in NCI-H460 cells. Using apoptosis model and combination analyses, we found that pomalidomide directly targeted ETFA, and increased ATP generation, thereby significantly promoting tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Specific knockdown of ETFA could effectively eliminate the promoting effect of pomalidomide on energy production. Furthermore, respiratory chain inhibitors can effectively block cell apoptosis induced by TRAIL and pomalidomide. These results suggested that pomalidomide may promote apoptosis by facilitating energy production by targeting ETFA and thus enhanced the anticancer effects of chemotherapeutic drugs. It is noteworthy that pomalidomide noticeably increased the anticancer efficacy of cisplatin (CDDP) in NCI-H460 xenograft model with the main mechanisms by inducing apoptosis. Collectively, our data not only provide new insights into the anticancer mechanisms of pomalidomide but also reflect translational prospects of combining pomalidomide with CDDP for NSCLC treatment.
以沙利度胺为代表的免疫调节药物（IMiDs）与其他化疗药物联合使用时，对肺癌患者显示出益处，这激发了人们探索将泊马度胺与另一种药物联合用于治疗肺癌的研究，因为泊马度胺比沙利度胺更有效。然而，可与泊马度胺联合使用以使患者受益的药物及其相关机制仍不清楚。在此，我们基于链霉亲和素下拉法进行了蛋白质组学分析，以鉴定泊马度胺在非小细胞肺癌（NSCLC）中的潜在靶点。在这项研究中，电子传递黄素蛋白α亚基（ETFA），一种参与呼吸链电子传递的重要酶，被鉴定为泊马度胺在NCI-H460细胞中的关键细胞靶点。通过凋亡模型和联合分析，我们发现泊马度胺直接靶向ETFA，并增加ATP生成，从而显著促进肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡。特异性敲低ETFA可有效消除泊马度胺对能量产生的促进作用。此外，呼吸链抑制剂可有效阻断TRAIL和泊马度胺诱导的细胞凋亡。这些结果表明，泊马度胺可能通过靶向ETFA促进能量产生来促进凋亡，从而增强化疗药物的抗癌效果。值得注意的是，在NCI-H460异种移植模型中，泊马度胺显著提高了顺铂（CDDP）的抗癌疗效，其主要机制是诱导凋亡。总体而言，我们的数据不仅为泊马度胺的抗癌机制提供了新的见解，也反映了泊马度胺与CDDP联合用于NSCLC治疗的转化前景。
