Malonate differentially affects cell survival and confers chemoresistance in cancer cells via the induction of p53-dependent autophagy
Malonate differentially affects cell survival and confers chemoresistance in cancer cells via the induction of p53-dependent autophagy
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DOI：
10.1016/j.bcp.2023.115950
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发表时间：
2023-12-05
影响因子：
5.8
通讯作者：
Liu，Yong
中科院分区：
文献类型：
--
作者：
Cui，Hao;Zhu，Bao;Liu，Yong
代谢网络与癌症信号和药物反应交织在一起。丙二酸盐是癌症的主要代谢物，也是琥珀酸脱氢酶（SDH）的竞争性抑制剂。最近的研究表明，丙二酸盐诱导神经母细胞瘤细胞活性氧（ROS）依赖性凋亡，但保护细胞免受缺血再灌注损伤。我们在这里揭示了丙二酸盐在癌细胞中调节细胞死亡和存活的差异。高剂量丙二酸触发ros依赖性细胞凋亡，低剂量丙二酸诱导细胞自噬并产生对多种化疗药物的耐药性。在机制上，我们的研究结果表明丙二酸盐增加p53的稳定性和转录上调自噬调节剂DRAM（损伤调节自噬调节剂），从而促进自噬。我们进一步证明，丙二酸盐相关的化学耐药需要自噬。总的来说，我们的研究结果表明丙二酸盐在癌症对应激源的反应中起着双重作用，并突出了p53诱导的自噬对丙二酸盐的促癌作用。
Metabolic network intertwines with cancerous signaling and drug responses. Malonate is a prevailing metabolite in cancer and a competitive inhibitor of succinate dehydrogenase (SDH). Recent studies showed that malonate induced reactive oxygen species (ROS)-dependent apoptosis in neuroblastoma cells, but protected cells from ischemia-reperfusion injury. We here revealed that malonate differentially regulated cell death and survival in cancer cells. While high-dose malonate triggered ROS-dependent apoptosis, the low-dose malonate induced autophagy and conferred resistance to multiple chemotherapeutic agents. Mechanistically, our results showed that malonate increased p53 stability and transcriptionally up-regulated autophagy modulator DRAM (damage-regulated autophagy modulator), thus promoting autophagy. We further proved that autophagy is required for malonate-associated chemoresistance. Collectively, our findings suggest that malonate plays a double-edge function in cancer response to stressors, and highlights a pro-cancer impact of p53-induced autophagy in response to malonate.