{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:58:20Z","timestamp":1792497500575,"version":"4.5.0"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA184918"],"award-info":[{"award-number":["R01CA184918"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA227622"],"award-info":[{"award-number":["R01CA227622"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P50CA098258"],"award-info":[{"award-number":["P50CA098258"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Exp Clin Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Uterine serous cancer (USC) is the most common non-endometrioid subtype of uterine cancer, and is also the most aggressive. Most patients will die of progressively chemotherapy-resistant disease, and the development of new therapies that can target USC remains a major unmet clinical need. This study sought to determine the molecular mechanism by which a novel unfavorable prognostic biomarker ryanodine receptor 1 (RYR1) identified in advanced USC confers their malignant phenotypes, and demonstrated the efficacy of targeting RYR1 by repositioned FDA-approved compounds in USC treatment.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>TCGA USC dataset was analyzed to identify top genes that are associated with patient survival or disease stage, and can be targeted by FDA-approved compounds. The top gene RYR1 was selected and the functional role of RYR1 in USC progression was determined by silencing and over-expressing RYR1 in USC cells in vitro and in vivo. The molecular mechanism and signaling networks associated with the functional role of RYR1 in USC progression were determined by reverse phase protein arrays (RPPA), Western blot, and transcriptomic profiling analyses. The efficacy of the repositioned compound dantrolene on USC progression was determined using both in vitro and in vivo models.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>High expression level of RYR1 in the tumors is associated with advanced stage of the disease. Inhibition of RYR1 suppressed proliferation, migration and enhanced apoptosis through Ca<jats:sup>2+<\/jats:sup>-dependent activation of AKT\/CREB\/PGC-1\u03b1 and AKT\/HK1\/2 signaling pathways, which modulate mitochondrial bioenergetics properties, including oxidative phosphorylation, ATP production, mitochondrial membrane potential, ROS production and TCA metabolites, and glycolytic activities in USC cells. Repositioned compound dantrolene suppressed USC progression and survival in mouse models.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>These findings provided insight into the mechanism by which RYR1 modulates the malignant phenotypes of USC and could aid in the development of dantrolene as a repurposed therapeutic agent for the treatment of USC to improve patient survival.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13046-022-02419-w","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T17:14:50Z","timestamp":1660238090000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Ryanodine receptor 1-mediated Ca2+ signaling and mitochondrial reprogramming modulate uterine serous cancer malignant phenotypes"],"prefix":"10.1186","volume":"41","author":[{"given":"Li","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Lam","family":"Au-Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsz-Lun","family":"Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sammy","family":"Ferri-Borgogno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barrett C.","family":"Lawson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suet-Ying","family":"Kwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen T.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vienna","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen H.","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay-Pong","family":"Yip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S. K.","family":"Sham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel C.","family":"Mok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"2419_CR1","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1097\/GCO.0b013e328334d8a3","volume":"22","author":"AN Fader","year":"2010","unstructured":"Fader AN, Boruta D, Olawaiye AB, Gehrig PA. Uterine papillary serous carcinoma: epidemiology, pathogenesis and management. Curr Opin Obstet Gynecol. 2010;22:21\u20139.","journal-title":"Curr Opin Obstet Gynecol"},{"key":"2419_CR2","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.ygyno.2009.06.011","volume":"115","author":"DM Boruta 2nd","year":"2009","unstructured":"Boruta DM 2nd, Gehrig PA, Fader AN, Olawaiye AB. Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol. 2009;115:142\u201353.","journal-title":"Gynecol Oncol"},{"key":"2419_CR3","first-page":"45","volume":"10","author":"JD Black","year":"2014","unstructured":"Black JD, English DP, Roque DM, Santin AD. Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer. Womens Health. 2014;10:45\u201357.","journal-title":"Womens Health"},{"key":"2419_CR4","doi-asserted-by":"crossref","unstructured":"Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-grade serous ovarian Cancer: basic sciences, clinical and therapeutic standpoints. Int J Mol Sci. 2019;20(4):952.","DOI":"10.3390\/ijms20040952"},{"key":"2419_CR5","doi-asserted-by":"crossref","unstructured":"Wallbillich JJ, Morris RT, Ali-Fehmi R. Comparing mutation frequencies for homologous recombination genes in uterine serous and high-grade serous ovarian carcinomas: a case for homologous recombination deficiency testing in uterine serous carcinoma. Gynecol Oncol. 2020;159(2):381-386.","DOI":"10.1016\/j.ygyno.2020.08.012"},{"key":"2419_CR6","doi-asserted-by":"publisher","first-page":"287","DOI":"10.3233\/CBM-2011-0167","volume":"9","author":"MA Merritt","year":"2010","unstructured":"Merritt MA, Cramer DW. Molecular pathogenesis of endometrial and ovarian cancer. Cancer Biomark. 2010;9:287\u2013305.","journal-title":"Cancer Biomark"},{"key":"2419_CR7","doi-asserted-by":"publisher","first-page":"4008","DOI":"10.18632\/oncotarget.14021","volume":"8","author":"K Brasseur","year":"2017","unstructured":"Brasseur K, Gevry N, Asselin E. Chemoresistance and targeted therapies in ovarian and endometrial cancers. Oncotarget. 2017;8:4008\u201342.","journal-title":"Oncotarget"},{"key":"2419_CR8","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.7150\/ijbs.24612","volume":"14","author":"H Xue","year":"2018","unstructured":"Xue H, Li J, Xie H, Wang Y. Review of drug repositioning approaches and resources. Int J Biol Sci. 2018;14:1232\u201344.","journal-title":"Int J Biol Sci"},{"key":"2419_CR9","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1080\/17460441.2020.1704729","volume":"15","author":"A Talevi","year":"2020","unstructured":"Talevi A, Bellera CL. Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics. Expert Opin Drug Discov. 2020;15:397\u2013401.","journal-title":"Expert Opin Drug Discov"},{"key":"2419_CR10","doi-asserted-by":"publisher","first-page":"26965","DOI":"10.1074\/jbc.272.43.26965","volume":"272","author":"BR Fruen","year":"1997","unstructured":"Fruen BR, Mickelson JR, Louis CF. Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors. J Biol Chem. 1997;272:26965\u201371.","journal-title":"J Biol Chem"},{"key":"2419_CR11","doi-asserted-by":"publisher","first-page":"13810","DOI":"10.1074\/jbc.M006104200","volume":"276","author":"F Zhao","year":"2001","unstructured":"Zhao F, Li P, Chen SR, Louis CF, Fruen BR. Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity. J Biol Chem. 2001;276:13810\u20136.","journal-title":"J Biol Chem"},{"key":"2419_CR12","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1111\/j.1365-2044.2004.03658.x","volume":"59","author":"T Krause","year":"2004","unstructured":"Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004;59:364\u201373.","journal-title":"Anaesthesia"},{"key":"2419_CR13","doi-asserted-by":"publisher","first-page":"668","DOI":"10.2174\/1871527317666180619162649","volume":"18","author":"Y Shi","year":"2019","unstructured":"Shi Y, Wang Y, Wei H. Dantrolene : from malignant hyperthermia to Alzheimer's disease. CNS Neurol Disord Drug Targets. 2019;18:668\u201376.","journal-title":"CNS Neurol Disord Drug Targets"},{"key":"2419_CR14","doi-asserted-by":"publisher","first-page":"241","DOI":"10.4065\/70.3.241","volume":"70","author":"DJ Wedel","year":"1995","unstructured":"Wedel DJ, Quinlan JG, Iaizzo PA. Clinical effects of intravenously administered dantrolene. Mayo Clin Proc. 1995;70:241\u20136.","journal-title":"Mayo Clin Proc"},{"key":"2419_CR15","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1007\/s10620-013-2938-9","volume":"59","author":"YJ Huang","year":"2014","unstructured":"Huang YJ, Frazier ML, Zhang N, Liu Q, Wei C. Reverse-phase protein array analysis to identify biomarker proteins in human pancreatic cancer. Dig Dis Sci. 2014;59:968\u201375.","journal-title":"Dig Dis Sci"},{"key":"2419_CR16","doi-asserted-by":"publisher","first-page":"C382","DOI":"10.1152\/ajpcell.00234.2012","volume":"304","author":"L Balasubramanian","year":"2013","unstructured":"Balasubramanian L, Lo CM, Sham JS, Yip KP. Remanent cell traction force in renal vascular smooth muscle cells induced by integrin-mediated mechanotransduction. Am J Physiol Cell Physiol. 2013;304:C382\u201391.","journal-title":"Am J Physiol Cell Physiol"},{"key":"2419_CR17","doi-asserted-by":"publisher","first-page":"R1586","DOI":"10.1152\/ajpregu.00025.2007","volume":"293","author":"L Balasubramanian","year":"2007","unstructured":"Balasubramanian L, Ahmed A, Lo CM, Sham JS, Yip KP. Integrin-mediated mechanotransduction in renal vascular smooth muscle cells: activation of calcium sparks. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1586\u201394.","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2419_CR18","doi-asserted-by":"publisher","first-page":"F540","DOI":"10.1152\/ajprenal.00544.2009","volume":"300","author":"KP Yip","year":"2011","unstructured":"Yip KP, Sham JS. Mechanisms of vasopressin-induced intracellular Ca2+ oscillations in rat inner medullary collecting duct. Am J Physiol Renal Physiol. 2011;300:F540\u20138.","journal-title":"Am J Physiol Renal Physiol"},{"key":"2419_CR19","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.1038\/ncomms5153","volume":"5","author":"J Suzuki","year":"2014","unstructured":"Suzuki J, Kanemaru K, Ishii K, Ohkura M, Okubo Y, Iino M. Imaging intraorganellar Ca2+ at subcellular resolution using CEPIA. Nat Commun. 2014;5:4153.","journal-title":"Nat Commun"},{"key":"2419_CR20","doi-asserted-by":"publisher","first-page":"3185","DOI":"10.1073\/pnas.051429498","volume":"98","author":"I Walev","year":"2001","unstructured":"Walev I, Bhakdi SC, Hofmann F, Djonder N, Valeva A, Aktories K, et al. Delivery of proteins into living cells by reversible membrane permeabilization with streptolysin-O. Proc Natl Acad Sci U S A. 2001;98:3185\u201390.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2419_CR21","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1152\/physrev.1997.77.3.699","volume":"77","author":"C Franzini-Armstrong","year":"1997","unstructured":"Franzini-Armstrong C, Protasi F. Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions. Physiol Rev. 1997;77:699\u2013729.","journal-title":"Physiol Rev"},{"key":"2419_CR22","doi-asserted-by":"publisher","first-page":"a003996","DOI":"10.1101\/cshperspect.a003996","volume":"2","author":"JT Lanner","year":"2010","unstructured":"Lanner JT, Georgiou DK, Joshi AD, Hamilton SL. Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol. 2010;2:a003996.","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2419_CR23","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1016\/S0006-3495(00)76381-8","volume":"79","author":"V Lukyanenko","year":"2000","unstructured":"Lukyanenko V, Gyorke I, Subramanian S, Smirnov A, Wiesner TF, Gyorke S. Inhibition of ca(2+) sparks by ruthenium red in permeabilized rat ventricular myocytes. Biophys J. 2000;79:1273\u201384.","journal-title":"Biophys J"},{"key":"2419_CR24","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.tcb.2018.02.009","volume":"28","author":"G Csordas","year":"2018","unstructured":"Csordas G, Weaver D, Hajnoczky G. Endoplasmic reticulum-mitochondrial Contactology: structure and signaling functions. Trends Cell Biol. 2018;28:523\u201340.","journal-title":"Trends Cell Biol"},{"key":"2419_CR25","doi-asserted-by":"publisher","first-page":"e430","DOI":"10.1038\/cddis.2012.171","volume":"3","author":"A Perelman","year":"2012","unstructured":"Perelman A, Wachtel C, Cohen M, Haupt S, Shapiro H, Tzur A. JC-1: alternative excitation wavelengths facilitate mitochondrial membrane potential cytometry. Cell Death Dis. 2012;3:e430.","journal-title":"Cell Death Dis"},{"key":"2419_CR26","first-page":"198","volume":"9","author":"F Bost","year":"2019","unstructured":"Bost F, Kaminski L. The metabolic modulator PGC-1alpha in cancer. Am J Cancer Res. 2019;9:198\u2013211.","journal-title":"Am J Cancer Res"},{"key":"2419_CR27","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.1242\/jeb.00241","volume":"206","author":"JE Wilson","year":"2003","unstructured":"Wilson JE. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol. 2003;206:2049\u201357.","journal-title":"J Exp Biol"},{"key":"2419_CR28","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1152\/advan.00052.2006","volume":"30","author":"H Liang","year":"2006","unstructured":"Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ. 2006;30:145\u201351.","journal-title":"Adv Physiol Educ"},{"key":"2419_CR29","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.1016\/j.bbamcr.2018.07.011","volume":"1865","author":"A Kushnir","year":"2018","unstructured":"Kushnir A, Wajsberg B, Marks AR. Ryanodine receptor dysfunction in human disorders. Biochim Biophys Acta Mol Cell Res. 2018;1865:1687\u201397.","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"2419_CR30","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/B978-0-444-64074-1.00038-0","volume":"157","author":"PM Hopkins","year":"2018","unstructured":"Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018;157:645\u201361.","journal-title":"Handb Clin Neurol"},{"key":"2419_CR31","doi-asserted-by":"publisher","first-page":"3208","DOI":"10.1161\/01.CIR.0000132472.98675.EC","volume":"109","author":"SE Lehnart","year":"2004","unstructured":"Lehnart SE, Wehrens XH, Laitinen PJ, Reiken SR, Deng SX, Cheng Z, et al. Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation. 2004;109:3208\u201314.","journal-title":"Circulation"},{"key":"2419_CR32","doi-asserted-by":"publisher","first-page":"17917","DOI":"10.1074\/jbc.270.30.17917","volume":"270","author":"LY Bourguignon","year":"1995","unstructured":"Bourguignon LY, Chu A, Jin H, Brandt NR. Ryanodine receptor-ankyrin interaction regulates internal Ca2+ release in mouse T-lymphoma cells. J Biol Chem. 1995;270:17917\u201322.","journal-title":"J Biol Chem"},{"key":"2419_CR33","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1002\/(SICI)1097-0045(20000515)43:3<205::AID-PROS6>3.0.CO;2-M","volume":"43","author":"P Mariot","year":"2000","unstructured":"Mariot P, Prevarskaya N, Roudbaraki MM, Le Bourhis X, Van Coppenolle F, Vanoverberghe K, et al. Evidence of functional ryanodine receptor involved in apoptosis of prostate cancer (LNCaP) cells. Prostate. 2000;43:205\u201314.","journal-title":"Prostate"},{"key":"2419_CR34","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1042\/BJ20040900","volume":"386","author":"DD Bose","year":"2005","unstructured":"Bose DD, Rahimian R, Thomas DW. Activation of ryanodine receptors induces calcium influx in a neuroblastoma cell line lacking calcium influx factor activity. Biochem J. 2005;386:291\u20136.","journal-title":"Biochem J"},{"key":"2419_CR35","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1016\/j.celrep.2017.02.001","volume":"18","author":"H Lu","year":"2017","unstructured":"Lu H, Chen I, Shimoda LA, Park Y, Zhang C, Tran L, et al. Chemotherapy-induced ca(2+) release stimulates breast Cancer stem cell enrichment. Cell Rep. 2017;18:1946\u201357.","journal-title":"Cell Rep"},{"key":"2419_CR36","doi-asserted-by":"publisher","first-page":"13653","DOI":"10.1073\/pnas.1103360108","volume":"108","author":"L Zhang","year":"2011","unstructured":"Zhang L, Liu Y, Song F, Zheng H, Hu L, Lu H, et al. Functional SNP in the microRNA-367 binding site in the 3'UTR of the calcium channel ryanodine receptor gene 3 (RYR3) affects breast cancer risk and calcification. Proc Natl Acad Sci U S A. 2011;108:13653\u20138.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2419_CR37","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1093\/cvr\/cvw067","volume":"111","author":"AH Lin","year":"2016","unstructured":"Lin AH, Sun H, Paudel O, Lin MJ, Sham JS. Conformation of ryanodine receptor-2 gates store-operated calcium entry in rat pulmonary arterial myocytes. Cardiovasc Res. 2016;111:94\u2013104.","journal-title":"Cardiovasc Res"},{"key":"2419_CR38","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/nrc.2017.18","volume":"17","author":"GR Monteith","year":"2017","unstructured":"Monteith GR, Prevarskaya N, Roberts-Thomson SJ. The calcium-cancer signalling nexus. Nat Rev Cancer. 2017;17:367\u201380.","journal-title":"Nat Rev Cancer"},{"key":"2419_CR39","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/cr.2017.155","volume":"28","author":"PE Porporato","year":"2018","unstructured":"Porporato PE, Filigheddu N, Pedro JMB, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018;28:265\u201380.","journal-title":"Cell Res"},{"key":"2419_CR40","doi-asserted-by":"publisher","first-page":"2519","DOI":"10.1016\/j.ejca.2004.07.009","volume":"40","author":"T Pejovic","year":"2004","unstructured":"Pejovic T, Ladner D, Intengan M, Zheng K, Fairchild T, Dillon D, et al. Somatic D-loop mitochondrial DNA mutations are frequent in uterine serous carcinoma. Eur J Cancer. 2004;40:2519\u201324.","journal-title":"Eur J Cancer"},{"key":"2419_CR41","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.ygyno.2015.02.003","volume":"137","author":"S Mabuchi","year":"2015","unstructured":"Mabuchi S, Kuroda H, Takahashi R, Sasano T. The PI3K\/AKT\/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol Oncol. 2015;137:173\u20139.","journal-title":"Gynecol Oncol"},{"key":"2419_CR42","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1016\/j.bbamcr.2011.03.010","volume":"1813","author":"X Zhang","year":"2011","unstructured":"Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011;1813:1978\u201386.","journal-title":"Biochim Biophys Acta"},{"key":"2419_CR43","doi-asserted-by":"publisher","first-page":"5853","DOI":"10.1038\/sj.onc.1207721","volume":"23","author":"DA Altomare","year":"2004","unstructured":"Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK, et al. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 2004;23:5853\u20137.","journal-title":"Oncogene"},{"key":"2419_CR44","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.ygyno.2019.01.012","volume":"153","author":"HJ Choi","year":"2019","unstructured":"Choi HJ, Heo JH, Park JY, Jeong JY, Cho HJ, Park KS, et al. A novel PI3K\/mTOR dual inhibitor, CMG002, overcomes the chemoresistance in ovarian cancer. Gynecol Oncol. 2019;153:135\u201348.","journal-title":"Gynecol Oncol"},{"key":"2419_CR45","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1016\/j.bpj.2017.09.008","volume":"113","author":"M Zhang","year":"2017","unstructured":"Zhang M, Jang H, Gaponenko V, Nussinov R. Phosphorylated calmodulin promotes PI3K activation by binding to the SH2 domains. Biophys J. 2017;113:1956\u201367.","journal-title":"Biophys J"},{"key":"2419_CR46","doi-asserted-by":"publisher","first-page":"32377","DOI":"10.1074\/jbc.273.49.32377","volume":"273","author":"K Du","year":"1998","unstructured":"Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt\/PKB. J Biol Chem. 1998;273:32377\u20139.","journal-title":"J Biol Chem"},{"key":"2419_CR47","first-page":"6107","volume":"14","author":"RP Matthews","year":"1994","unstructured":"Matthews RP, Guthrie CR, Wailes LM, Zhao X, Means AR, McKnight GS. Calcium\/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression. Mol Cell Biol. 1994;14:6107\u201316.","journal-title":"Mol Cell Biol"},{"key":"2419_CR48","doi-asserted-by":"publisher","first-page":"180","DOI":"10.3389\/fonc.2017.00180","volume":"7","author":"G Pedriali","year":"2017","unstructured":"Pedriali G, Rimessi A, Sbano L, Giorgi C, Wieckowski MR, Previati M, et al. Regulation of endoplasmic reticulum-mitochondria ca(2+) transfer and its importance for anti-Cancer therapies. Front Oncol. 2017;7:180.","journal-title":"Front Oncol"},{"key":"2419_CR49","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/nature10234","volume":"476","author":"JM Baughman","year":"2011","unstructured":"Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 2011;476:341\u20135.","journal-title":"Nature"},{"key":"2419_CR50","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/nature10230","volume":"476","author":"D De Stefani","year":"2011","unstructured":"De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011;476:336\u201340.","journal-title":"Nature"},{"key":"2419_CR51","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s00395-007-0666-z","volume":"102","author":"C Maack","year":"2007","unstructured":"Maack C, O'Rourke B. Excitation-contraction coupling and mitochondrial energetics. Basic Res Cardiol. 2007;102:369\u201392.","journal-title":"Basic Res Cardiol"},{"key":"2419_CR52","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1152\/physrev.00026.2013","volume":"94","author":"DB Zorov","year":"2014","unstructured":"Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94:909\u201350.","journal-title":"Physiol Rev"},{"key":"2419_CR53","doi-asserted-by":"publisher","first-page":"171","DOI":"10.3389\/fonc.2017.00171","volume":"7","author":"C White","year":"2017","unstructured":"White C. The regulation of tumor cell invasion and metastasis by endoplasmic reticulum-to-mitochondrial ca(2+) transfer. Front Oncol. 2017;7:171.","journal-title":"Front Oncol"},{"key":"2419_CR54","doi-asserted-by":"publisher","first-page":"199","DOI":"10.3389\/fonc.2017.00199","volume":"7","author":"G Bustos","year":"2017","unstructured":"Bustos G, Cruz P, Lovy A, Cardenas C. Endoplasmic reticulum-mitochondria calcium communication and the regulation of mitochondrial metabolism in Cancer: a novel potential target. Front Oncol. 2017;7:199.","journal-title":"Front Oncol"},{"key":"2419_CR55","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1158\/0008-5472.CAN-08-3359","volume":"69","author":"H Pelicano","year":"2009","unstructured":"Pelicano H, Lu W, Zhou Y, Zhang W, Chen Z, Hu Y, et al. Mitochondrial dysfunction and reactive oxygen species imbalance promote breast cancer cell motility through a CXCL14-mediated mechanism. Cancer Res. 2009;69:2375\u201383.","journal-title":"Cancer Res"},{"key":"2419_CR56","doi-asserted-by":"publisher","first-page":"4683","DOI":"10.1038\/sj.onc.1209595","volume":"25","author":"RB Robey","year":"2006","unstructured":"Robey RB, Hay N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene. 2006;25:4683\u201396.","journal-title":"Oncogene"},{"key":"2419_CR57","doi-asserted-by":"publisher","first-page":"215","DOI":"10.18632\/genesandcancer.179","volume":"9","author":"KMK Al-Taee","year":"2018","unstructured":"Al-Taee KMK, Zepp M, Berger I, Berger MR, Adwan H. Pancreatic carcinoma cells colonizing the liver modulate the expression of their extracellular matrix genes. Genes Cancer. 2018;9:215\u201331.","journal-title":"Genes Cancer"},{"key":"2419_CR58","doi-asserted-by":"publisher","first-page":"27","DOI":"10.4103\/0976-0105.177703","volume":"7","author":"AB Nair","year":"2016","unstructured":"Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7:27\u201331.","journal-title":"J Basic Clin Pharm"},{"key":"2419_CR59","doi-asserted-by":"publisher","first-page":"4763","DOI":"10.1074\/jbc.271.9.4763","volume":"271","author":"S Schmoelzl","year":"1996","unstructured":"Schmoelzl S, Leeb T, Brinkmeier H, Brem G, Brenig B. Regulation of tissue-specific expression of the skeletal muscle ryanodine receptor gene. J Biol Chem. 1996;271:4763\u20139.","journal-title":"J Biol Chem"},{"key":"2419_CR60","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s12935-015-0221-1","volume":"15","author":"KO Alfarouk","year":"2015","unstructured":"Alfarouk KO, Stock CM, Taylor S, Walsh M, Muddathir AK, Verduzco D, et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int. 2015;15:71.","journal-title":"Cancer Cell Int"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-022-02419-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-022-02419-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-022-02419-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T18:02:53Z","timestamp":1660240973000},"score":1,"resource":{"primary":{"URL":"https:\/\/jeccr.biomedcentral.com\/articles\/10.1186\/s13046-022-02419-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,11]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["2419"],"URL":"https:\/\/doi.org\/10.1186\/s13046-022-02419-w","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,11]]},"assertion":[{"value":"13 October 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 June 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal work was performed in accordance with protocols approved by the Institutional Animal Care and Use Committee of The University of Texas MD Anderson Cancer Center. The study is compliant with all relevant ethical regulations regarding animal research.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"242"}}