Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
Division of Endocrinology and Center for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Biochim Biophys Acta Mol Basis Dis. 2022 Oct 1;1868(10):166455. doi: 10.1016/j.bbadis.2022.166455. Epub 2022 Jun 6.
Autophagy inhibition is currently considered a novel therapeutic strategy for cancer treatment. Lipoic acid (LA), a naturally occurring compound found in all prokaryotic and eukaryotic cells, inhibits breast cancer cell growth; however, the effect of LA on autophagy-mediated breast cancer cell death remains unknown. Our study identified that LA blocks autophagic flux by inhibiting autophagosome-lysosome fusion and lysosome activity which increases the accumulation of autophagosomes in MCF-7 and MDA-MB231 cells, leading to cell death of breast cancer cells. Interestingly, autophagic flux blockade limits the recycling of cellular fuels, resulting in insufficient substrates for cellular bioenergetics. Therefore, LA impairs cellular bioenergetics by the inhibition of mitochondrial function and glycolysis. We show that LA-induced ROS generation is responsible for the blockade of autophagic flux and cellular bioenergetics in breast cancer cells. Moreover, LA-mediated blockade of autophagic flux and ROS generation may interfere with the regulation of the BCSCs/progenitor phenotype. Here, we demonstrate that LA inhibits mammosphere formation and subpopulation of BCSCs. Together, these results implicate that LA acts as a prooxidant, potent autophagic flux inhibitor, and causes energetic impairment, which may lead to cell death in breast cancer cells/BCSCs.
自噬抑制被认为是癌症治疗的一种新的治疗策略。硫辛酸（LA）是一种存在于所有原核和真核细胞中的天然化合物，可抑制乳腺癌细胞的生长；然而，LA 对自噬介导的乳腺癌细胞死亡的影响尚不清楚。我们的研究表明，LA 通过抑制自噬体-溶酶体融合和溶酶体活性来阻断自噬流，这导致 MCF-7 和 MDA-MB231 细胞中自噬体的积累增加，从而导致乳腺癌细胞死亡。有趣的是，自噬流阻断限制了细胞燃料的再循环，导致细胞生物能量学的底物不足。因此，LA 通过抑制线粒体功能和糖酵解来损害细胞生物能量学。我们表明，LA 诱导的 ROS 生成负责阻断乳腺癌细胞中的自噬流和细胞生物能量学。此外，LA 介导的自噬流阻断和 ROS 生成可能干扰 BCSC/祖细胞表型的调节。在这里，我们证明 LA 抑制了乳腺球体的形成和 BCSC 的亚群。总之，这些结果表明 LA 作为一种促氧化剂、有效的自噬流抑制剂，以及导致能量损伤，可能导致乳腺癌细胞/BCSC 死亡。
