Similar articles

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.

二氯乙酸联合雷帕霉素协同抑制肿瘤进程

[1]AraújoNC, Sampaio Goncalves de Lucena SB, da Silveira RiojaS, 2014. Effect of rapamycin on spleen size in longstanding renal transplant recipients. Transplant Proc, 46(5):1319-1323.

[2]BaiZS, PengYL, YeXY, et al., 2022. Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(2):89-101.

[3]BenjaminD, ColombiM, MoroniC, et al., 2011. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov, 10(11):868-880.

[4]BerettaL, GingrasAC, SvitkinYV, et al., 1996. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J, 15(3):658-664.

[5]BernardiR, GuernahI, JinD, et al., 2006. PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR. Nature, 442(7104):779-785.

[6]CaoWG, YacoubS, ShiverickKT, et al., 2008. Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate, 68(11):1223-1231.

[7]FanQW, AksoyO, WongRA, et al., 2017. A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. Cancer Cell, 31(3):424-435.

[8]GhobrialIM, SiegelDS, VijR, et al., 2016. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: a phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or waldenström’s macroglobulinemia. Am J Hematol, 91(4):400-405.

[9]GubaM, von BreitenbuchP, SteinbauerM, et al., 2002. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med, 8(2):128-135.

[10]HolnessMJ, SugdenMC, 2003. Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem Soc Trans, 31(6):1143-1151.

[11]HsiehAC, LiuY, EdlindMP, et al., 2012. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature, 485(7396):55-61.

[12]JacintoE, LoewithR, SchmidtA, et al., 2004. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol, 6(11):1122-1128.

[13]JacobsKE, VisserBC, GayerG, 2012. Changes in spleen volume after resection of hepatic colorectal metastases. Clin Radiol, 67(10):982-987.

[14]KaplonJ, ZhengL, MeisslK, et al., 2013. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature, 498(7452):109-112.

[15]KimJ, GuanKL, 2019. mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol, 21(1):63-71.

[16]LammingDW, YeL, KatajistoP, et al., 2012. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science, 335(6076):1638-1643.

[17]LevyJMM, TowersCG, ThorburnA, 2017. Targeting autophagy in cancer. Nat Rev Cancer, 17(9):528-542.

[18]LorussoPM, 2016. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol, 34(31):3803-3815.

[19]LucidoCT, MiskiminsWK, VermeerPD, 2018. Propranolol promotes glucose dependence and synergizes with dichloroacetate for anti-cancer activity in HNSCC. Cancers (Basel), 10(12):476.

[20]LuengoA, LiZQ, GuiDY, et al., 2021. Increased demand for NAD⁺ relative to ATP drives aerobic glycolysis. Mol Cell, 81(4):691-707.e6.

[21]MenonS, ManningBD, 2008. Common corruption of the mTOR signaling network in human tumors. Oncogene, 27:S43-S51.

[22]PatelMS, NemeriaNS, FureyW, et al., 2014. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem, 289(24):16615-16623.

[23]PhungTL, ZivK, DabydeenD, et al., 2006. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell, 10(2):159-170.

[24]RobitailleAM, ChristenS, ShimobayashiM, et al., 2013. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science, 339(6125):1320-1323.

[25]Rodrik-OutmezguineVS, ChandarlapatyS, PaganoNC, et al., 2011. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov, 1(3):248-259.

[26]Rodrik-OutmezguineVS, OkaniwaM, YaoZ, et al., 2016. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature, 534(7606):272-276.

[27]SabatiniDM, Erdjument-BromageH, LuiM, et al., 1994. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell, 78(1):35-43.

[28]SarbassovDD, AliSM, SenguptaS, et al., 2006. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell, 22(2):159-168.

[29]Škorja MilićN, DolinarK, MišK, et al., 2021. Suppression of pyruvate dehydrogenase kinase by dichloroacetate in cancer and skeletal muscle cells is isoform specific and partially independent of HIF-1α. Int J Mol Sci, 22(16):8610.

[30]SutendraG, DromparisP, KinnairdA, et al., 2013. Mitochondrial activation by inhibition of PDKII suppresses HIF1α signaling and angiogenesis in cancer. Oncogene, 32(13):1638-1650.

[31]TataranniT, PiccoliC, 2019. Dichloroacetate (DCA) and cancer: an overview towards clinical applications. Oxid Med Cell Longev, 2019:8201079.

[32]TsoSC, QiXB, GuiWJ, et al., 2014. Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. J Biol Chem, 289(7):4432-4443.

[33]ValvezanAJ, TurnerM, BelaidA, et al., 2017. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability. Cancer Cell, 32(5):624-638.e5.

[34]VermaA, LamYM, LeungYC, et al., 2019. Combined use of arginase and dichloroacetate exhibits anti-proliferative effects in triple negative breast cancer cells. J Pharm Pharmacol, 71(3):306-315.

[35]WuJG, ZhaoYL, ParkYK, et al., 2018. Loss of PDK4 switches the hepatic NF‍-‍κB/TNF pathway from pro-survival to pro-apoptosis. Hepatology, 68(3):1111-1124.

[36]YangHJ, JiangXL, LiBR, et al., 2017. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature, 552(7685):368-373.

[37]YangWC, PangDJ, ChenMN, et al., 2021. Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation. Dev Cell, 56(6):811-825.e6.

[38]ZhangS, QianGQ, ZhangQQ, et al., 2019. mTORC2 suppresses GSK3-dependent snail degradation to positively regulate cancer cell invasion and metastasis. Cancer Res, 79(14):3725-3736.

[39]ZhuangHQ, BaiJ, ChangJY, et al., 2016. MTOR inhibition reversed drug resistance after combination radiation with erlotinib in lung adenocarcinoma. Oncotarget, 7(51):84688-84694.