Inhibition of Stearoyl-CoA Desaturase 1 Potentiates Anti-tumor Activity of Amodiaquine in Non-small Cell Lung Cancer
Inhibition of Stearoyl-CoA Desaturase 1 Potentiates Anti-tumor Activity of Amodiaquine in Non-small Cell Lung Cancer
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DOI：
10.1248/bpb.b21-00843
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发表时间：
2022-04-01
影响因子：
2
通讯作者：
Qiao, Shuxi
中科院分区：
文献类型：
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作者：
Hu, Xiaolei;Xiang, Jiangning;Qiao, Shuxi
非小细胞肺癌(NSCLC)是癌症相关死亡的主要原因之一，治疗方案很少。在不利的肿瘤微环境下，自噬是维持肿瘤细胞存活和增殖的重要代谢适应机制。因此，靶向自噬活性为非小细胞肺癌的治疗提供了一个有希望的机会。在这里，我们发现阿莫地喹(AQ)增加了A549肺癌细胞的自噬小体数量和LC3BH和P62的蛋白水平，这表明AQ阻断了自噬通量。为了确定与AQ处理抑制自噬相关的关键代谢脆弱性，我们随后在A549肺癌细胞中进行了有或没有AQ的转录组学分析，发现硬脂酰辅酶A去饱和酶1(SCD1)是AQ处理后表达最高的基因之一。AQ在蛋白和mRNA水平均可诱导SCD_1的表达，提示SCD_1可能是AQ治疗的潜在治疗靶点。A939572联合应用A939572抑制SCD1后，在细胞增殖实验和小鼠肺癌异种移植模型中显示出很强的协同抗癌效果。综上所述，我们的研究证实SCD1可能成为AQ暴露抑制自噬的新的治疗靶点。抑制自噬和抑制SCD1的联合治疗在体内和体外均取得了协同抗肿瘤作用。这种联合治疗方法可能是治疗非小细胞肺癌的一种有前途的策略。
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer related death with few therapeutic treatment options. Under adverse tumor microenvironment, autophagy is an important mechanism of metabolic adaptations to sustain the survival and proliferation of tumor cells. Therefore, targeting autophagic activity represents a promising opportunity for NSCLC treatment. Here, we found that amodiaquine (AQ) increased autophagosome numbers and LC3BH and p62 at protein levels in A549 lung cancer cells suggesting the blockade of autophagic flux by AQ. To identify the key metabolic vulnerability associated with autophagy inhibition by AQ treatment, we then performed transcriptomics analysis in the presence or absence of AQ in A549 lung cancer cells and found stearoyl-CoA desaturase 1 (SCD1) was one of the most highly upregulated with AQ exposure. The induction of SCD1 by AQ exposure at both protein and mRNA level suggests that SCD1 could represent a potential therapeutic target of AQ treatment. Treatment of AQ in combination with SCD1 inhibition by A939572 demonstrated robust synergistic anti-cancer efficacy in cell proliferation assay and a lung cancer mouse xenograft model. Taken together, our study identified SCD1 could be a new therapeutic target upon autophagy inhibition by AQ exposure. Combinational treatment of autophagy inhibition and SCD1 inhibition achieves synergistic anti-tumor effect both in vitro and in vivo. This combinational approach could be a promising strategy for NSCLC treatment.