Abstract
Mammalian target of rapamycin (mTOR) controls cellular anabolism, and mTOR signaling is hyperactive in most cancer cells. As a result, inhibition of mTOR signaling benefits cancer patients. Rapamycin is a US Food and Drug Administration (FDA)-approved drug, a specific mTOR complex 1 (mTORC1) inhibitor, for the treatment of several different types of cancer. However, rapamycin is reported to inhibit cancer growth rather than induce apoptosis. Pyruvate dehydrogenase complex (PDHc) is the gatekeeper for mitochondrial pyruvate oxidation. PDHc inactivation has been observed in a number of cancer cells, and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide (NAD+) exhaustion. In this paper, we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells. This inactivation reduces the sensitivity of cancer cells’ response to rapamycin. As a result, rebooting PDHc activity with dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, promotes cancer cells’ susceptibility to rapamycin treatment in vitro and in vivo.
摘要
哺乳动物雷帕霉素靶蛋白 (mTOR) 控制细胞的合成代谢, 并且在大多数的肿瘤细胞中 mTOR 信号通路高度活化, 因此抑制 mTOR 信号通路对癌症患者有益. 雷帕霉素是一种美国食品药品监督管理局 (FDA) 批准的临床一线药物, 是 mTORC1 的特异性抑制剂, 用于治疗多种不同类型的癌症. 然而, 研究发现雷帕霉素仅抑制肿瘤细胞的增殖并不引起细胞的凋亡. 丙酮酸脱氢酶复合体 (PDHc) 在线粒体丙酮酸氧化过程起着决定作用. 许多肿瘤细胞中的 PDHc 处于失活状态, 这一变化可以使肿瘤细胞免于衰老和 NAD+耗竭. 本研究中, 雷帕霉素处理细胞导致依赖 mTOR 信号通路抑制的丙酸脱氢酶 α1 (PDHA1) 磷酸化水平升高, 并导致 PDHc 酶活降低. PDHc 失活直接引起肿瘤细胞对雷帕霉素敏感度下降. 因此, 在体内和体外的实验中通过使用丙酮酸脱氢酶激酶 (PDK) 的抑制剂二氯乙酸 (DCA) 可以重新激活 PDHc 的活力, 进而增加肿瘤细胞对雷帕霉素的敏感性.
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Acknowledgments
This work was supported by the National Key Research and Development Program of China (No. 2022YFA0806503), the National Natural Science Foundation of China (No. 81972625), the Dalian Science and Technology Innovation Funding (No. 2019J12SN52), and the Liaoning Revitalization Talents Program (No. XLYC2002035), China.
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Huan CHEN and Hai-long PIAO conceived the project, designed and performed most of the experiments and the data analysis, and wrote the manuscript with input from all other authors. Hai-long PIAO supervised the project. Kunimg LIANG performed the most of experiments. Huan CHEN, Kunimg LIANG, and Cong HOU provided significant intellectual input. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Huan CHEN, Kunming LIANG, Cong HOU, and Hailong PIAO declare that they have no conflict of interest.
All work performed with animals was approved by the Medical Animal Care and Use Committee of China Medical University, Shenyang, China (No. KT2020061).
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Chen, H., Liang, K., Hou, C. et al. Dichloroacetic acid and rapamycin synergistically inhibit tumor progression. J. Zhejiang Univ. Sci. B 24, 397–405 (2023). https://doi.org/10.1631/jzus.B2200356
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DOI: https://doi.org/10.1631/jzus.B2200356
Key words
- Dichloroacetic acid (DCA)
- Rapamycin
- Pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1)
- Mammalian target of rapamycin (mTOR)