Castelli Serena, Ciccarone Fabio, De Falco Pamela, Ciriolo Maria Rosa
Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, Rome, 00133, Italy.
Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, Rome, 00133, Italy; IRCCS San Raffaele Roma, Via di Val Cannuta, 247, Rome, 00166, Italy.
Cancer Lett. 2023 Feb 1;554:216010. doi: 10.1016/j.canlet.2022.216010. Epub 2022 Nov 17.
Alterations in lipid catabolism have been broadly described in cancer cells and show tumor-type specific effects on proliferation and cell survival. The factor(s) responsible for this heterogeneity is currently unknown and represents the main limitation in the development of therapeutic interventions that impair lipid metabolism. In this study, we focused on hexanoic acid, a medium-chain fatty acid, that can quickly boost oxidative metabolism by passively crossing mitochondrial membranes. We demonstrated that the antioxidant adaptation of cancer cells to increased fatty acid oxidation is predictive of the proliferative outcome. By interfering with SOD1 expression and glutathione homeostasis, we verified that mitochondrial fatty acid oxidation has antitumor effects in cancer cells that efficiently buffer ROS. In contrast, increased ROS levels promote proliferation in cells with an imbalanced antioxidant response. In addition, an increase in mitochondrial mass and mitophagy activation were observed, respectively. Overall, these data demonstrate that the capacity to manage ROS from mitochondrial oxidative metabolism determines whether lipid catabolism is advantageous or detrimental for cancer cells.
癌细胞中脂质分解代谢的改变已被广泛描述，并且对增殖和细胞存活表现出肿瘤类型特异性影响。导致这种异质性的因素目前尚不清楚，这是损害脂质代谢的治疗干预措施开发中的主要限制。在本研究中，我们聚焦于己酸，一种中链脂肪酸，它可以通过被动穿过线粒体膜快速促进氧化代谢。我们证明癌细胞对脂肪酸氧化增加的抗氧化适应可预测增殖结果。通过干扰超氧化物歧化酶1（SOD1）的表达和谷胱甘肽稳态，我们证实线粒体脂肪酸氧化在能有效缓冲活性氧（ROS）的癌细胞中具有抗肿瘤作用。相反，ROS水平升高会促进抗氧化反应失衡的细胞增殖。此外，分别观察到线粒体质量增加和线粒体自噬激活。总体而言，这些数据表明处理线粒体氧化代谢产生的ROS的能力决定了脂质分解代谢对癌细胞是有利还是有害。
