{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:47:09Z","timestamp":1791172029743,"version":"4.1.0"},"reference-count":50,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,11,1]]},"abstract":"<jats:p>Uterine leiomyomas (ULs), benign tumors of the myometrium, are the number one indication for hysterectomies in the United States due to a lack of an effective alternative therapy. ULs show activation of the pro-survival AKT pathway compared with normal myometrium; however, substantial data directly linking AKT to UL cell survival are lacking. We hypothesized that AKT promotes UL cell survival and that it is a viable target for inhibiting UL growth. We used the investigational AKT inhibitor MK-2206, currently in phase II trials, on cultured primary human UL and myometrial cells, immortalized leiomyoma cells, and in leiomyoma grafts grown under the kidney capsule in mice. MK-2206 inhibited AKT and PRAS40 phosphorylation but did not regulate serum- and glucocorticoid-induced kinase and ERK1\/2, demonstrating its specificity for AKT. MK-2206 reduced UL cell viability and decreased UL tumor volumes. UL cells exhibited disruption of mitochondrial structures and underwent cell death that was independent of caspases. Additionally, mammalian target of rapamycin and p70S6K phosphorylation were reduced, indicating that mammalian target of rapamycin complex 1 signaling was compromised by AKT inhibition in UL cells. MK-2206 also induced autophagy in UL cells. Pretreatment of primary UL cells with 3-methyladenine enhanced MK-2206-mediated UL cell death, whereas knockdown of ATG5 and\/or ATG7 did not significantly influence UL cell viability in the presence of MK-2206. Our data provide molecular evidence for the involvement of AKT in UL cell survival and suggest that AKT inhibition by MK-2206 may be a viable option to consider for the treatment of ULs.<\/jats:p>","DOI":"10.1210\/en.2013-1389","type":"journal-article","created":{"date-parts":[[2013,9,4]],"date-time":"2013-09-04T03:44:48Z","timestamp":1378266288000},"page":"4046-4057","source":"Crossref","is-referenced-by-count":43,"title":["MK-2206, an AKT Inhibitor, Promotes Caspase-Independent Cell Death and Inhibits Leiomyoma Growth"],"prefix":"10.1210","volume":"154","author":[{"given":"Elizabeth C.","family":"Sefton","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (E.C.S., W.Q., V.S., T.K., D.C., J.J.K.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenan","family":"Qiang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (E.C.S., W.Q., V.S., T.K., D.C., J.J.K.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanida","family":"Serna","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (E.C.S., W.Q., V.S., T.K., D.C., J.J.K.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kurita","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (E.C.S., W.Q., V.S., T.K., D.C., J.J.K.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Jun","family":"Wei","sequence":"first","affiliation":[{"name":"Division of Reproductive Biology Research, and Department of Pathology (J.-J.W.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debabrata","family":"Chakravarti","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (E.C.S., W.Q., V.S., T.K., D.C., J.J.K.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Julie","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (E.C.S., W.Q., V.S., T.K., D.C., J.J.K.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"issue":"4","key":"2020071611573784300_B1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1093\/ajcp\/94.4.435","article-title":"The frequency of uterine leiomyomas","volume":"94","author":"Cramer","year":"1990","journal-title":"Am J Clin Pathol"},{"issue":"3","key":"2020071611573784300_B2","doi-asserted-by":"crossref","first-page":"211.e1","DOI":"10.1016\/j.ajog.2011.12.002","article-title":"The estimated annual cost of uterine leiomyomata in the United States","volume":"206","author":"Cardozo","year":"2012","journal-title":"Am J Obstet Gynecol"},{"issue":"7","key":"2020071611573784300_B3","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrc839","article-title":"The phosphatidylinositol 3-kinase AKT pathway in human cancer","volume":"2","author":"Vivanco","year":"2002","journal-title":"Nat Rev Cancer"},{"issue":"4\u20135","key":"2020071611573784300_B4","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.jsbmb.2003.09.007","article-title":"Differential expression of Akt\/protein kinase B, Bcl-2 and Bax proteins in human leiomyoma and myometrium","volume":"87","author":"Kov\u00e1cs","year":"2003","journal-title":"J Steroid Biochem Mol Biol"},{"issue":"2","key":"2020071611573784300_B5","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jsbmb.2006.08.006","article-title":"Phosphorylation of PTEN (phosphatase and tensin homologue deleted on chromosome ten) protein is enhanced in human fibromyomatous uteri","volume":"103","author":"Kov\u00e1cs","year":"2007","journal-title":"J Steroid Biochem Mol Biol"},{"issue":"8","key":"2020071611573784300_B6","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1016\/j.fertnstert.2009.03.100","article-title":"Changes related to phosphatidylinositol 3-kinase\/Akt signaling in leiomyomas: possible involvement of glycogen synthase kinase 3\u03b1 and cyclin D2 in the pathophysiology","volume":"93","author":"Karra","year":"2010","journal-title":"Fertil Steril"},{"issue":"2","key":"2020071611573784300_B7","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/modpathol.3800283","article-title":"Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata","volume":"18","author":"Wei","year":"2005","journal-title":"Mod Pathol"},{"issue":"6","key":"2020071611573784300_B8","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1016\/j.fertnstert.2007.10.083","article-title":"Expression of insulin-like growth factors (IGFs) and IGF signaling: molecular complexity in uterine leiomyomas","volume":"91","author":"Peng","year":"2009","journal-title":"Fertil Steril"},{"issue":"5","key":"2020071611573784300_B9","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1210\/jc.2008-2093","article-title":"Progestins activate the AKT pathway in leiomyoma cells and promote survival","volume":"94","author":"Hoekstra","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"issue":"16","key":"2020071611573784300_B10","doi-asserted-by":"crossref","first-page":"5353","DOI":"10.1158\/1078-0432.CCR-10-1948","article-title":"PM02734 (elisidepsin) induces caspase-independent cell death associated with features of autophagy, inhibition of the Akt\/mTOR signaling pathway, and activation of death-associated protein kinase","volume":"17","author":"Ling","year":"2011","journal-title":"Clin Cancer Res"},{"issue":"50","key":"2020071611573784300_B11","doi-asserted-by":"crossref","first-page":"21695","DOI":"10.1073\/pnas.1009179107","article-title":"Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis","volume":"107","author":"Trichonas","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"issue":"24","key":"2020071611573784300_B12","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1161\/01.CIR.0000130647.29030.90","article-title":"Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning","volume":"109","author":"Uchiyama","year":"2004","journal-title":"Circulation"},{"issue":"11","key":"2020071611573784300_B13","doi-asserted-by":"crossref","first-page":"3178","DOI":"10.1016\/j.bmcl.2008.04.074","article-title":"Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model","volume":"18","author":"Bilodeau","year":"2008","journal-title":"Bioorg Med Chem Lett"},{"issue":"11","key":"2020071611573784300_B14","doi-asserted-by":"crossref","first-page":"e14124","DOI":"10.1371\/journal.pone.0014124","article-title":"Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo","volume":"5","author":"Meng","year":"2010","journal-title":"PLoS One"},{"issue":"7","key":"2020071611573784300_B15","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1158\/1535-7163.MCT-09-1012","article-title":"MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo","volume":"9","author":"Hirai","year":"2010","journal-title":"Mol Cancer Ther"},{"issue":"35","key":"2020071611573784300_B16","doi-asserted-by":"crossref","first-page":"4688","DOI":"10.1200\/JCO.2011.35.5263","article-title":"First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors","volume":"29","author":"Yap","year":"2011","journal-title":"J Clin Oncol"},{"issue":"6","key":"2020071611573784300_B17","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1210\/en.2009-1225","article-title":"Progesterone is essential for maintenance and growth of uterine leiomyoma","volume":"151","author":"Ishikawa","year":"2010","journal-title":"Endocrinology"},{"issue":"1","key":"2020071611573784300_B18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.cancergencyto.2006.05.003","article-title":"Karyotypic characteristics of human uterine leiomyoma and myometrial cell lines following telomerase induction","volume":"170","author":"Varella-Garcia","year":"2006","journal-title":"Cancer Genet Cytogenet"},{"issue":"7","key":"2020071611573784300_B19","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"AKT\/PKB signaling: navigating downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"issue":"38","key":"2020071611573784300_B20","doi-asserted-by":"crossref","first-page":"35243","DOI":"10.1074\/jbc.C100319200","article-title":"The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase\/protein kinase B pathway","volume":"276","author":"Arico","year":"2001","journal-title":"J Biol Chem"},{"issue":"5938","key":"2020071611573784300_B21","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1126\/science.1172308","article-title":"RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis","volume":"325","author":"Zhang","year":"2009","journal-title":"Science"},{"issue":"7","key":"2020071611573784300_B22","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1158\/0008-5472.CAN-10-2889","article-title":"eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206","volume":"71","author":"Cheng","year":"2011","journal-title":"Cancer Res"},{"key":"2020071611573784300_B23","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1038\/leu.2012.136","article-title":"Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia","volume":"26","author":"Simioni","year":"2012","journal-title":"Leukemia"},{"issue":"4","key":"2020071611573784300_B24","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"issue":"36","key":"2020071611573784300_B25","doi-asserted-by":"crossref","first-page":"21920","DOI":"10.1074\/jbc.271.36.21920","article-title":"Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation","volume":"271","author":"Kohn","year":"1996","journal-title":"J Biol Chem"},{"issue":"2","key":"2020071611573784300_B26","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ceb.2009.12.008","article-title":"Role of autophagy in suppression of inflammation and cancer","volume":"22","author":"White","year":"2010","journal-title":"Curr Opin Cell Biol"},{"issue":"4","key":"2020071611573784300_B27","doi-asserted-by":"crossref","first-page":"322","DOI":"10.7150\/ijbs.5925","article-title":"Chloroquine promotes the anticancer effect of TACE in a rabbit VX2 liver tumor model","volume":"9","author":"Gao","year":"2013","journal-title":"Int J Biol Sci"},{"issue":"7","key":"2020071611573784300_B28","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1097\/PAS.0b013e3182863fa8","article-title":"LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar cardiomyopathy: a study of 3 cases","volume":"37","author":"Daniels","year":"2013","journal-title":"Am J Surg Pathol"},{"issue":"4\u20135","key":"2020071611573784300_B29","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s10735-010-9283-5","article-title":"Protective effects of crude garlic by reducing iron-mediated oxidative stress, proliferation and autophagy in rats","volume":"41","author":"Nahdi","year":"2010","journal-title":"J Mol Histol"},{"issue":"4","key":"2020071611573784300_B30","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.ajog.2006.02.020","article-title":"Health care resource use for uterine fibroid tumors in the United States","volume":"195","author":"Flynn","year":"2006","journal-title":"Am J Obstet Gynecol"},{"issue":"4","key":"2020071611573784300_B31","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.bpobgyn.2008.03.001","article-title":"Medical management of fibroids","volume":"22","author":"Sankaran","year":"2008","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"issue":"6","key":"2020071611573784300_B32","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1073\/pnas.1215759110","article-title":"Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway","volume":"110","author":"Varghese","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"2020071611573784300_B33","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.fertnstert.2013.03.007","article-title":"Complex networks of multiple factors in the pathogenesis of uterine leiomyoma","volume":"100","author":"Islam","year":"2013","journal-title":"Fertil Steril"},{"issue":"2","key":"2020071611573784300_B34","doi-asserted-by":"crossref","first-page":"176.e1","DOI":"10.1016\/j.ajog.2006.09.037","article-title":"Requirements of phosphatidylinositol-3 kinase and mammalian target of rapamycin for estrogen-induced proliferation in uterine leiomyoma- and myometrium-derived cell lines","volume":"196","author":"Yin","year":"2007","journal-title":"Am J Obstet Gynecol"},{"key":"2020071611573784300_B35","doi-asserted-by":"crossref","first-page":"15s","DOI":"10.1200\/jco.2009.27.15_suppl.3503","article-title":"A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST)","volume":"27","author":"Tolcher","year":"2009","journal-title":"J Clin Oncol"},{"issue":"20","key":"2020071611573784300_B36","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1158\/1078-0432.CCR-12-1141","article-title":"Biomarkers of response to Akt inhibitor MK-2206 in breast cancer","volume":"18","author":"Sangai","year":"2012","journal-title":"Clin Cancer Res"},{"issue":"2","key":"2020071611573784300_B37","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.ygyno.2005.08.044","article-title":"A small molecule compound inhibits AKT pathway in ovarian cancer cell lines","volume":"100","author":"Tang","year":"2006","journal-title":"Gynecol Oncol"},{"issue":"10","key":"2020071611573784300_B38","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1038\/sj.bjc.6602214","article-title":"Inhibition of AKT survival pathway by a small molecule inhibitor in human endometrial cancer cells","volume":"91","author":"Jin","year":"2004","journal-title":"Br J Cancer"},{"issue":"2","key":"2020071611573784300_B39","doi-asserted-by":"crossref","first-page":"E173","DOI":"10.1210\/jc.2011-1054","article-title":"The Akt inhibitor MK2206 synergizes, but perifosine antagonizes, the BRAF(V600E) inhibitor PLX4032 and the MEK1\/2 inhibitor AZD6244 in the inhibition of thyroid cancer cells","volume":"97","author":"Liu","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"13","key":"2020071611573784300_B40","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1158\/1078-0432.CCR-11-3321","article-title":"Combination of an allosteric Akt Inhibitor MK-2206 with etoposide or rapamycin enhances the antitumor growth effect in neuroblastoma","volume":"18","author":"Li","year":"2012","journal-title":"Clin Cancer Res"},{"issue":"10","key":"2020071611573784300_B41","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/nrm2970","article-title":"Molecular mechanisms of necroptosis: an ordered cellular explosion","volume":"11","author":"Vandenabeele","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"1","key":"2020071611573784300_B42","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.cellsig.2007.07.010","article-title":"PKB and the mitochondria: AKTing on apoptosis","volume":"20","author":"Parcellier","year":"2008","journal-title":"Cell Signal"},{"issue":"17","key":"2020071611573784300_B43","doi-asserted-by":"crossref","first-page":"6566","DOI":"10.1073\/pnas.1201608109","article-title":"Bax regulates primary necrosis through mitochondrial dynamics","volume":"109","author":"Whelan","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2020071611573784300_B44","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/cvr\/cvq113","article-title":"Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning","volume":"88","author":"Hausenloy","year":"2010","journal-title":"Cardiovasc Res"},{"issue":"1","key":"2020071611573784300_B45","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00404-012-2245-2","article-title":"Gene and protein expression of progesterone receptor isoforms A and B, p53 and p21 in myometrium and uterine leiomyoma","volume":"286","author":"Lora","year":"2012","journal-title":"Arch Gynecol Obstet"},{"issue":"3","key":"2020071611573784300_B46","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1083\/jcb.200202130","article-title":"Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death","volume":"158","author":"Cregan","year":"2002","journal-title":"J Cell Biol"},{"issue":"8","key":"2020071611573784300_B47","doi-asserted-by":"crossref","first-page":"4154","DOI":"10.4049\/jimmunol.1102739","article-title":"Regulation of inflammatory response by 3-methyladenine involves the coordinative actions on Akt and glycogen synthase kinase 3\u03b2 rather than autophagy","volume":"189","author":"Lin","year":"2012","journal-title":"J Immunol"},{"issue":"1","key":"2020071611573784300_B48","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1476-5381.2012.02110.x","article-title":"The autophagic inhibitor 3-methyladenine potently stimulates PKA-dependent lipolysis in adipocytes","volume":"168","author":"Heckmann","year":"2013","journal-title":"Br J Pharmacol"},{"issue":"2","key":"2020071611573784300_B49","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.mce.2011.05.044","article-title":"The role of progesterone signaling in the pathogenesis of uterine leiomyoma","volume":"358","author":"Kim","year":"2012","journal-title":"Mol Cell Endocrinol"},{"issue":"7","key":"2020071611573784300_B50","doi-asserted-by":"crossref","first-page":"e41593","DOI":"10.1371\/journal.pone.0041593","article-title":"Inhibition of AKT with the orally active allosteric AKT inhibitor, MK-2206, sensitizes endometrial cancer cells to progestin","volume":"7","author":"Pant","year":"2012","journal-title":"PLoS One"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/154\/11\/4046\/13635467\/endo4046.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/154\/11\/4046\/13635467\/endo4046.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T13:24:43Z","timestamp":1646486683000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/154\/11\/4046\/2422709"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,11,1]]},"references-count":50,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2013,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2013-1389","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,11,1]]}}}