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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

Mitochondrial Calcium Uniporter (MCU) that Modulates Mitochondrial Calcium Uptake and Facilitates Endometrial Cancer Progression through Interaction with VDAC1

Author(s): Hongyan Xiao, Lijun Ma*, Jie Ding, Honghong Wang, Xiaofang Bi, Fengmei Tan and Wenhua Piao*

Volume 24, Issue 3, 2024

Published on: 27 September, 2023

Page: [354 - 367] Pages: 14

DOI: 10.2174/1568009624666230912095526

Price: $65

Abstract

Background: Although endometrial cancer represents a frequently diagnosed malignancy of the female reproductive tract, we know very little about the factors that control endometrial cancer.

Objective: Our study was presented to investigate the function of MCU in endometrial tumorigenesis and the molecular mechanisms involved.

Materials and Methods: A total of 94 endometrial cancer patients were recruited into our cohort. MCU and VDAC1 expression was examined in tumor and normal tissues via immunohistochemistry and immunofluorescence. Associations of MCU and VDAC1 expression with clinicopathological characteristics were evaluated. After transfection with shRNA targeting MCU or full-length MCU plasmids, clone formation, wound healing, transwell and MitoTracker Red staining were separately presented in Ishikawa and RL95-2 cells. Moreover, Western blotting or immunofluorescence was utilized to examine the expression of MCU, VDAC1, Na+/Ca2+/Li+ exchanger (NCLX), and β-catenin under VDAC1 knockdown and/or MCU overexpression or knockdown.

Results: MCU and VDAC1 expression were prominently up-regulated in endometrial cancer tissues and were significantly associated with histological grade, depth of myometrial invasion and lymph node status. MCU up-regulation enhanced clone formation, migration, and mitochondrial activity of endometrial cancer cells. The opposite results were investigated when MCU was silenced. MCU or VDAC1 silencing reduced the expression of MCU, VDAC1, NCLX, and β-catenin. Moreover, VDAC1 knockdown alleviated the promoting effect of MCU overexpression on the above proteins.

Conclusion: This investigation demonstrated that MCU-induced mitochondrial calcium uptake plays a critical role in endometrial tumorigenesis through interaction with VDAC1.

Keywords: Endometrial cancer, MCU, VDAC1, proliferation, migration, mitochondrial membrane potential, mitochondrial calcium uptake.

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[1]
Ryan, N.A.J.; Glaire, M.A.; Blake, D.; Cabrera-Dandy, M.; Evans, D.G.; Crosbie, E.J. The proportion of endometrial cancers associated with Lynch syndrome: A systematic review of the literature and meta-analysis. Genet. Med., 2019, 21(10), 2167-2180.
[http://dx.doi.org/10.1038/s41436-019-0536-8] [PMID: 31086306]
[2]
Wang, Y.; Yin, L.; Sun, X. CircRNA hsa_circ_0002577 accelerates endometrial cancer progression through activating IGF1R/PI3K/Akt pathway. J. Exp. Clin. Cancer Res., 2020, 39(1), 169.
[http://dx.doi.org/10.1186/s13046-020-01679-8] [PMID: 32847606]
[3]
Song, Y.; Wang, M.; Tong, H.; Tan, Y.; Hu, X.; Wang, K.; Wan, X. Plasma exosomes from endometrial cancer patients contain LGALS3BP to promote endometrial cancer progression. Oncogene, 2021, 40(3), 633-646.
[http://dx.doi.org/10.1038/s41388-020-01555-x] [PMID: 33208911]
[4]
Westin, S.N.; Fellman, B.; Sun, C.C.; Broaddus, R.R.; Woodall, M.L.; Pal, N.; Urbauer, D.L.; Ramondetta, L.M.; Schmeler, K.M.; Soliman, P.T.; Fleming, N.D.; Burzawa, J.K.; Nick, A.M.; Milbourne, A.M.; Yuan, Y.; Lu, K.H.; Bodurka, D.C.; Coleman, R.L.; Yates, M.S. Prospective phase II trial of levonorgestrel intrauterine device: Nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer. Am. J. Obstet. Gynecol., 2021, 224(2), 191.e1-191.e15.
[http://dx.doi.org/10.1016/j.ajog.2020.08.032] [PMID: 32805208]
[5]
van den Heerik, A.S.V.M.; Horeweg, N.; de Boer, S.M.; Bosse, T.; Creutzberg, C.L. Adjuvant therapy for endometrial cancer in the era of molecular classification: Radiotherapy, chemoradiation and novel targets for therapy. Int. J. Gynecol. Cancer, 2021, 31(4), 594-604.
[http://dx.doi.org/10.1136/ijgc-2020-001822] [PMID: 33082238]
[6]
Daw, C.C.; Ramachandran, K.; Enslow, B.T.; Maity, S.; Bursic, B.; Novello, M.J.; Rubannelsonkumar, C.S.; Mashal, A.H.; Ravichandran, J.; Bakewell, T.M.; Wang, W.; Li, K.; Madaris, T.R.; Shannon, C.E.; Norton, L.; Kandala, S.; Caplan, J.; Srikantan, S.; Stathopulos, P.B.; Reeves, W.B.; Madesh, M. Lactate elicits ER-mitochondrial Mg2+ dynamics to integrate cellular metabolism. Cell, 2020, 183(2), 474-489.e17.
[http://dx.doi.org/10.1016/j.cell.2020.08.049] [PMID: 33035451]
[7]
Cui, C.; Merritt, R.; Fu, L.; Pan, Z. Targeting calcium signaling in cancer therapy. Acta Pharm. Sin. B, 2017, 7(1), 3-17.
[http://dx.doi.org/10.1016/j.apsb.2016.11.001] [PMID: 28119804]
[8]
Katoshevski, T.; Ben-Kasus Nissim, T.; Sekler, I. Recent studies on NCLX in health and diseases. Cell Calcium, 2021, 94, 102345.
[http://dx.doi.org/10.1016/j.ceca.2020.102345] [PMID: 33508514]
[9]
Kostic, M.; Katoshevski, T.; Sekler, I. Allosteric regulation of NCLX by mitochondrial membrane potential links the metabolic state and Ca2+ signaling in mitochondria. Cell Rep., 2018, 25(12), 3465-3475.e4.
[http://dx.doi.org/10.1016/j.celrep.2018.11.084] [PMID: 30566870]
[10]
Liu, Y.; Jin, M.; Wang, Y.; Zhu, J.; Tan, R.; Zhao, J.; Ji, X.; Jin, C.; Jia, Y.; Ren, T.; Xing, J. MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth. Signal Transduct. Target. Ther., 2020, 5(1), 59.
[http://dx.doi.org/10.1038/s41392-020-0155-5] [PMID: 32371956]
[11]
Palty, R.; Silverman, W.F.; Hershfinkel, M.; Caporale, T.; Sensi, S.L.; Parnis, J.; Nolte, C.; Fishman, D.; Shoshan-Barmatz, V.; Herrmann, S.; Khananshvili, D.; Sekler, I. NCLX is an essential component of mitochondrial Na + /Ca 2+ exchange. Proc. Natl. Acad. Sci. USA, 2010, 107(1), 436-441.
[http://dx.doi.org/10.1073/pnas.0908099107] [PMID: 20018762]
[12]
Marchi, S.; Giorgi, C.; Galluzzi, L.; Pinton, P. Ca2+ Fluxes and Cancer. Mol. Cell, 2020, 78(6), 1055-1069.
[http://dx.doi.org/10.1016/j.molcel.2020.04.017] [PMID: 32559424]
[13]
Delierneux, C.; Kouba, S.; Shanmughapriya, S.; Potier-Cartereau, M.; Trebak, M.; Hempel, N. Mitochondrial calcium regulation of redox signaling in cancer. Cells, 2020, 9(2), 432.
[http://dx.doi.org/10.3390/cells9020432] [PMID: 32059571]
[14]
Zeng, F.; Chen, X.; Cui, W.; Wen, W.; Lu, F.; Sun, X.; Ma, D.; Yuan, Y.; Li, Z.; Hou, N.; Zhao, H.; Bi, X.; Zhao, J.; Zhou, J.; Zhang, Y.; Xiao, R.P.; Cai, J.; Zhang, X. RIPK1 binds MCU to mediate induction of mitochondrial Ca2+ uptake and promotes colorectal oncogenesis. Cancer Res., 2018, 78(11), 2876-2885.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-3082] [PMID: 29531160]
[15]
Chen, L.; Sun, Q.; Zhou, D.; Song, W.; Yang, Q.; Ju, B.; Zhang, L.; Xie, H.; Zhou, L.; Hu, Z.; Yao, H.; Zheng, S.; Wang, W. HINT2 triggers mitochondrial Ca2+ influx by regulating the mitochondrial Ca2+ uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer. Cancer Lett., 2017, 411, 106-116.
[http://dx.doi.org/10.1016/j.canlet.2017.09.020] [PMID: 28947137]
[16]
Zheng, X.; Lu, S.; He, Z.; Huang, H.; Yao, Z.; Miao, Y.; Cai, C.; Zou, F. MCU-dependent negative sorting of miR-4488 to extracellular vesicles enhances angiogenesis and promotes breast cancer metastatic colonization. Oncogene, 2020, 39(46), 6975-6989.
[http://dx.doi.org/10.1038/s41388-020-01514-6] [PMID: 33067576]
[17]
Li, C.J.; Lin, H.Y.; Ko, C.J.; Lai, J.C.; Chu, P.Y. A novel biomarker driving poor-prognosis liver cancer: Overexpression of the mitochondrial calcium gatekeepers. Biomedicines, 2020, 8(11), 451.
[http://dx.doi.org/10.3390/biomedicines8110451] [PMID: 33114428]
[18]
Sun, Y.; Li, M.; Liu, G.; Zhang, X.; Zhi, L.; Zhao, J.; Wang, G. The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism. J. Cancer Res. Clin. Oncol., 2020, 146(5), 1139-1152.
[http://dx.doi.org/10.1007/s00432-020-03179-w] [PMID: 32152662]
[19]
Miao, Y.; Wang, X.; Lai, Y.; Lin, W.; Huang, Y.; Yin, H.; Hou, R.; Zhang, F. Mitochondrial calcium uniporter promotes cell proliferation and migration in esophageal cancer. Oncol. Lett., 2021, 22(3), 686.
[http://dx.doi.org/10.3892/ol.2021.12947] [PMID: 34434285]
[20]
Wu, R.; Zuo, W.; Xu, X.; Bi, L.; Zhang, C.; Chen, H.; Liu, H. MCU that is transcriptionally regulated by Nrf2 augments malignant biological behaviors in oral squamous cell carcinoma cells. BioMed Res. Int., 2021, 2021, 1-17.
[http://dx.doi.org/10.1155/2021/6650791] [PMID: 34189138]
[21]
Bazhin, A.A.; Sinisi, R.; De Marchi, U.; Hermant, A.; Sambiagio, N.; Maric, T.; Budin, G.; Goun, E.A. A bioluminescent probe for longitudinal monitoring of mitochondrial membrane potential. Nat. Chem. Biol., 2020, 16(12), 1385-1393.
[http://dx.doi.org/10.1038/s41589-020-0602-1] [PMID: 32778841]
[22]
Alevriadou, B.R.; Patel, A.; Noble, M.; Ghosh, S.; Gohil, V.M.; Stathopulos, P.B.; Madesh, M. Molecular nature and physiological role of the mitochondrial calcium uniporter channel. Am. J. Physiol. Cell Physiol., 2021, 320(4), C465-C482.
[http://dx.doi.org/10.1152/ajpcell.00502.2020] [PMID: 33296287]
[23]
Vais, H.; Payne, R.; Paudel, U.; Li, C.; Foskett, J.K. Coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca 2+ uptake. Proc. Natl. Acad. Sci. USA, 2020, 117(35), 21731-21739.
[http://dx.doi.org/10.1073/pnas.2005976117] [PMID: 32801213]
[24]
Kostic, M.; Sekler, I. Functional properties and mode of regulation of the mitochondrial Na+/Ca2+ exchanger, NCLX. Semin. Cell Dev. Biol., 2019, 94, 59-65.
[http://dx.doi.org/10.1016/j.semcdb.2019.01.009] [PMID: 30658153]
[25]
Pathak, T.; Gueguinou, M.; Walter, V.; Delierneux, C.; Johnson, M.T.; Zhang, X.; Xin, P.; Yoast, R.E.; Emrich, S.M.; Yochum, G.S.; Sekler, I.; Koltun, W.A.; Gill, D.L.; Hempel, N.; Trebak, M. Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis. eLife, 2020, 9, e59686.
[http://dx.doi.org/10.7554/eLife.59686] [PMID: 32914752]
[26]
Shteinfer-Kuzmine, A.; Verma, A.; Arif, T.; Aizenberg, O.; Paul, A.; Shoshan-Barmaz, V. Mitochondria and nucleus cross‐talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer. IUBMB Life, 2021, 73(3), 492-510.
[http://dx.doi.org/10.1002/iub.2407] [PMID: 33179373]
[27]
Grun, B.; Benjamin, E.; Sinclair, J.; Timms, J.F.; Jacobs, I.J.; Gayther, S.A.; Dafou, D. Three-dimensional in vitro cell biology models of ovarian and endometrial cancer. Cell Prolif., 2009, 42(2), 219-228.
[http://dx.doi.org/10.1111/j.1365-2184.2008.00579.x] [PMID: 19222485]
[28]
Fang, Y.; Liu, J.; Zhang, Q.; She, C.; Zheng, R.; Zhang, R.; Chen, Z.; Chen, C.; Wu, J. Overexpressed VDAC1 in breast cancer as a novel prognostic biomarker and correlates with immune infiltrates. World J. Surg. Oncol., 2022, 20(1), 211.
[http://dx.doi.org/10.1186/s12957-022-02667-2] [PMID: 35729567]
[29]
Zerbib, E.; Arif, T.; Shteinfer-Kuzmine, A.; Chalifa-Caspi, V.; Shoshan-Barmatz, V. VDAC1 silencing in cancer cells leads to metabolic reprogramming that modulates tumor microenvironment. Cancers, 2021, 13(11), 2850.
[http://dx.doi.org/10.3390/cancers13112850] [PMID: 34200480]
[30]
Zhang, C.; Hua, Y.; Qiu, H.; Liu, T.; Long, Q.; Liao, W.; Qiu, J.; Wang, N.; Chen, M.; Shi, D.; Yan, Y.; Xie, C.; Deng, W.; Li, T.; Li, Y. KMT2A regulates cervical cancer cell growth through targeting VDAC1. Aging, 2020, 12(10), 9604-9620.
[http://dx.doi.org/10.18632/aging.103229] [PMID: 32436862]
[31]
Huang, Q.; Ma, B.; Su, Y.; Chan, K.; Qu, H.; Huang, J.; Wang, D.; Qiu, J.; Liu, H.; Yang, X.; Wang, Z. miR-197-3p represses the proliferation of prostate cancer by regulating the VDAC1/AKT/β-catenin signaling axis. Int. J. Biol. Sci., 2020, 16(8), 1417-1426.
[http://dx.doi.org/10.7150/ijbs.42019] [PMID: 32210729]
[32]
Luo, L.; Xiong, Y.; Jiang, N.; Zhu, X.; Wang, Y.; Lv, Y.; Xie, Y. VDAC1 as a target in cisplatin anti-tumor activity through promoting mitochondria fusion. Biochem. Biophys. Res. Commun., 2021, 560, 52-58.
[http://dx.doi.org/10.1016/j.bbrc.2021.04.104] [PMID: 33971568]
[33]
Li, Y.; Kang, J.; Fu, J.; Luo, H.; Liu, Y.; Li, Y.; Sun, L. PGC1α promotes cisplatin resistance in ovarian cancer by regulating the HSP70/HK2/VDAC1 signaling pathway. Int. J. Mol. Sci., 2021, 22(5), 2537.
[http://dx.doi.org/10.3390/ijms22052537] [PMID: 33802591]
[34]
Zhang, Y.; Wang, X. Targeting the Wnt/β-catenin signaling pathway in cancer. J. Hematol. Oncol., 2020, 13(1), 165.
[http://dx.doi.org/10.1186/s13045-020-00990-3] [PMID: 33276800]

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