PI3K-Akt-mTOR and MAPK signaling pathways in polycystic ovarian syndrome, uterine leiomyomas and endometriosis: An update

Gynecological Endocrinology

Volumn 28, Issue 3, 2012, Pages 175-181

  Makker, Annu ^a   Goel, Madhu Mati ^a   Das, Vinita ^a   Agarwal, Anjoo ^a  

^a KING GEORGE'S MEDICAL UNIVERSITY   (India)

Author keywords

Endometriosis; MAPK; PCOS; PI3K Akt mTOR; Uterine leiomyoma

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; CHORIONIC GONADOTROPIN; CYPROTERONE ACETATE; DIAZOXIDE; ESTROGEN; FOLLITROPIN; GENISTEIN; INSULIN; LEUPRORELIN; LUTEINIZING HORMONE; MAMMALIAN TARGET OF RAPAMYCIN; METFORMIN; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; PHOSPHATIDYLINOSITOL 3 KINASE; PIOGLITAZONE; PROMEGESTONE; PROTEIN KINASE B; RALOXIFENE; RAPAMYCIN DERIVATIVE; STRESS ACTIVATED PROTEIN KINASE; UNCLASSIFIED DRUG; WAY 129327;

ARTICLE; ENDOMETRIOSIS; HUMAN; HYPERANDROGENISM; MORBIDITY; NONHUMAN; OVARY POLYCYSTIC DISEASE; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN TARGETING; SIGNAL TRANSDUCTION; UTERUS MYOMA;

ENDOMETRIOSIS; FEMALE; HUMANS; LEIOMYOMA; MITOGEN-ACTIVATED PROTEIN KINASES; PHOSPHATIDYLINOSITOL 3-KINASES; POLYCYSTIC OVARY SYNDROME; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; UTERINE NEOPLASMS;

EID: 84856846355     PISSN: 09513590     EISSN: 14730766     Source Type: Journal    
DOI: 10.3109/09513590.2011.583955     Document Type: Article

References (70)

1. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-1657. (Pubitemid 34579158)
2. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004;167:399-403. (Pubitemid 39489047)
3. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and infammation. Physiol Rev 2001;81:807-869. (Pubitemid 32267078)
4. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 2004;5:875-885. (Pubitemid 39486539)
5. Force T, Bonventre JV. Growth factors and mitogen-activated protein kinases. Hypertension 1998;31:152-161.
6. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008;118:3065-3074.
7. Silfen ME, Denburg MR, Manibo AM, Lobo RA, Jafe R, Ferin M, Levine LS, Oberfeld SE. Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents. J Clin Endocrinol Metab 2003;88:4682-4688. (Pubitemid 37357512)
8. Goodarzi MO, Jones MR, Chen YD, Azziz R. First evidence of genetic association between AKT2 and polycystic ovary syndrome. Diabetes Care 2008;31:2284-2287.
9. Diao FY, Xu M, Hu Y, Li J, Xu Z, Lin M, Wang L, et al. The molecular characteristics of polycystic ovary syndrome (PCOS) ovary defned by human ovary cDNA microarray. J Mol Endocrinol 2004; 33:59-72. (Pubitemid 39206348)
10. Goodarzi MO, Xu N, Cui J, Guo X, Chen YI, Azziz R. Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA), a candidate gene for polycystic ovary syndrome. Hum Reprod 2008;23:1214-1219. (Pubitemid 351757330)
11. Möhlig M, Jürgens A, Spranger J, Hofmann K, Weickert MO, Schlösser H W, Schill T, et al. The androgen receptor CAG repeat modifes the impact of testosterone on insulin resistance in women with polycystic ovary syndrome. Eur J Endocrinol 2006;155:127-130. (Pubitemid 44103380)
12. Wu J, Zhu Y, Jiang Y, Cao Y. Efects of metformin and ethinyl estradiol-cyproterone acetate on clinical, endocrine and metabolic factors in women with polycystic ovary syndrome. Gynecol Endocrinol 2008;24:392-398. (Pubitemid 352032232)
13. Kim JJ, Choi YM, Hong MA, Hwang SS, Yoon SH, Chae SJ, Jee BC, et al. Phosphatidylinositol 3-kinase p85alpha regulatory subunit gene Met326Ile polymorphism in women with polycystic ovary syndrome. Hum Reprod 2009;24:1184-1190.
14. Allemand MC, Irving BA, Asmann YW, Klaus KA, Tatpati L, Coddington CC, Nair KS. Efect of testosterone on insulin stimulated IRS1 Ser phosphorylation in primary rat myotubes-a potential model for PCOS-related insulin resistance. PLoS ONE 2009;4:e4274.
15. Kayampilly P P, Menon KM. Follicle-stimulating hormone increases tuberin phosphorylation and mammalian target of rapamycin signaling through an extracellular signal-regulated kinase-dependent pathway in rat granulosa cells. Endocrinology 2007;148:3950-3957. (Pubitemid 47105853)
16. Fukuda S, Orisaka M, Tajima K, Hattori K, Kotsuji F. Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP Kinase in bovine theca cells. J Ovarian Res 2009;2:17.
17. Nelson-Degrave VL, Wickenheisser JK, Hendricks KL, Asano T, Fujishiro M, Legro RS, Kimball SR, et al. Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome. Mol Endocrinol 2005;19:379-390. (Pubitemid 40223462)
18. Yen H W, Jakimiuk AJ, Munir I, Magofn DA. Selective alterations in insulin receptor substrates-1,-2 and-4 in theca but not granulosa cells from polycystic ovaries. Mol Hum Reprod 2004;10:473-479. (Pubitemid 39136803)
19. Munir I, Geller DH, deBruin CE, Magofn DA. Dysregulation of GSK3B activity in polycystic ovarian syndrome (PCOS) theca: a mechanism to promote excessive androgen biosynthesis in PCOS. In Proceedings of the 88th Annual Meeting of the Endocrine Society. Boston, MA: Washington, DC Endocrine Society; 2006.
20. Sonntag B, Götte M, Wülfng P, Schüring AN, Kiesel L, Greb RR. Metformin alters insulin signaling and viability of human granulosa cells. Fertil Steril 2005;84 Suppl 2:1173-1179. (Pubitemid 41396543)
21. Legro RS, Barnhart HX, Schlaf WD, Carr BR, Diamond MP, Carson SA, Steinkampf M P, et al.; Reproductive Medicine Network. Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J Clin Endocrinol Metab 2008;93:792-800. (Pubitemid 351398555)
22. Rice S, Pellatt L, Ramanathan K, Whitehead SA, Mason HD. Metformin inhibits aromatase via an extracellular signal-regulated kinase-mediated pathway. Endocrinology 2009;150:4794-4801.
23. Lima MH, Souza LC, Caperuto LC, Bevilacqua E, Gasparetti AL, Zanuto R, Saad MJ, Carvalho CR. Up-regulation of the phosphatidylinositol 3-kinase/protein kinase B pathway in the ovary of rats by chronic treatment with hCG and insulin. J Endocrinol 2006;190:451-459. (Pubitemid 44288381)
24. Iwase A, Goto M, Harata T, Takigawa S, Nakahara T, Suzuki K, Manabe S, Kikkawa F. Insulin attenuates the insulin-like growth factor-I (IGF-I)-Akt pathway, not IGF-I-extracellularly regulated kinase pathway, in luteinized granulosa cells with an increase in PTEN. J Clin Endocrinol Metab 2009;94:2184-2191.
25. Yan M, Wang J, Wu X, Hou L, Kuang H, Wang Y. Induction of insulin resistance by phosphatidylinositol-3-kinase inhibitor in porcine granulosa cells. Fertil Steril 2009;92:2119-2121.
26. Quezada S, Avellaira C, Johnson MC, Gabler F, Fuentes A, Vega M. Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome. Fertil Steril 2006;85:1017-1026.
27. Avellaira C, Villavicencio A, Bacallao K, Gabler F, Wells P, Romero C, Vega M. Expression of molecules associated with tissue homeostasis in secretory endometria from untreated women with polycystic ovary syndrome. Hum Reprod 2006;21:3116-3121. (Pubitemid 44811612)
28. Villavicencio A, Goyeneche A, Telleria C, Bacallao K, Gabler F, Fuentes A, Vega M. Involvement of Akt, Ras and cell cycle regulators in the potential development of endometrial hyperplasia in women with polycystic ovarian syndrome. Gynecol Oncol 2009;115:102-107.
29. Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation- implications for a novel treatment strategy. Gynecol Oncol 2010;116:92-98.
30. Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab 2001;281:E392-E399.
31. Skov V, Glintborg D, Knudsen S, Tan Q, Jensen T, Kruse TA, Beck-Nielsen H, Højlund K. Pioglitazone enhances mitochondrial biogenesis and ribosomal protein biosynthesis in skeletal muscle in polycystic ovary syndrome. PLoS ONE 2008;3:e2466.
32. Corbould A, Zhao H, Mirzoeva S, Aird F, Dunaif A. Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. Diabetes 2006;55:751-759. (Pubitemid 43343232)
33. Rajkhowa M, Brett S, Cuthbertson DJ, Lipina C, Ruiz-Alcaraz AJ, Tomas GE, Logie L, et al. Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo. Biochem J 2009;418:665-671.
34. Seow KM, Juan CC, Hsu YP, Hwang JL, Huang LW, Ho LT. Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery. Hum Reprod 2007;22:1003-1010.
35. Yin XJ, Wang G, Khan-Dawood FS. Requirements of phosphatidylinositol-3 kinase and mammalian target of rapamycin for estrogen-induced proliferation in uterine leiomyoma-and myometrium-derived cell lines. Am J Obstet Gynecol 2007;196:176.e1-176.e5.
36. Nierth-Simpson EN, Martin MM, Chiang TC, Melnik LI, Rhodes LV, Muir SE, Burow ME, McLachlan JA. Human uterine smooth muscle and leiomyoma cells difer in their rapid 17beta-estradiol signaling: implications for proliferation. Endocrinology 2009;150:2436-2445.
37. Hermon TL, Moore AB, Yu L, Kissling GE, Castora FJ, Dixon D. Estrogen receptor alpha (ERalpha) phospho-serine-118 is highly expressed in human uterine leiomyomas compared to matched myometrium. Virchows Arch 2008;453:557-569.
38. Di X, Yu L, Moore AB, Castro L, Zheng X, Hermon T, Dixon D. A low concentration of genistein induces estrogen receptor-alpha and insulin-like growth factor-I receptor interactions and proliferation in uterine leiomyoma cells. Hum Reprod 2008;23:1873-1883. (Pubitemid 352019996)
39. Yu L, Saile K, Swartz CD, He H, Zheng X, Kissling GE, Di X, et al. Diferential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas. Mol Med 2008;14:264-275. (Pubitemid 351785699)
40. Orcy RB, Brum I, da Silva RS, Kucharski LC, Corleta HE, Capp E. Insulin receptor tyrosine kinase activity and substrate 1 (IRS-1) expression in human myometrium and leiomyoma. Eur J Obstet Gynecol Reprod Biol 2005;123:107-110. (Pubitemid 41563103)
41. Chegini N, Kornberg L. Gonadotropin releasing hormone analogue therapy alters signal transduction pathways involving mitogen-activated protein and focal adhesion kinases in leiomyoma. J Soc Gynecol Investig 2003;10:21-26. (Pubitemid 36051094)
42. Ding L, Xu J, Luo X, Chegini N. Gonadotropin releasing hormone and transforming growth factor beta activate mitogen-activated protein kinase/extracellularly regulated kinase and diferentially regulate fbronectin, type I collagen, and plasminogen activator inhibitor-1 expression in leiomyoma and myometrial smooth muscle cells. J Clin Endocrinol Metab 2004;89:5549-5557. (Pubitemid 39518439)
43. Mesquita FS, Dyer SN, Heinrich DA, Bulun SE, Marsh EE, Nowak RA. Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. Biol Reprod 2010;82:341-351.
44. Kovács KA, Lengyel F, Környei JL, Vértes Z, Szabó I, Sümegi B, Vértes M. Diferential expression of Akt/protein kinase B, Bcl-2 and Bax proteins in human leiomyoma and myometrium. J Steroid Biochem Mol Biol 2003;87:233-240. (Pubitemid 38036957)
45. Bifulco G, Miele C, Pellicano M, Trencia A, Ferraioli M, Paturzo F, Tommaselli GA, et al. Molecular mechanisms involved in GnRH analogue-related apoptosis for uterine leiomyomas. Mol Hum Reprod 2004;10:43-48. (Pubitemid 38195964)
46. Palomba S, Orio F Jr, Russo T, Falbo A, Tolino A, Lombardi G, Cimini V, Zullo F. Antiproliferative and proapoptotic efects of raloxifene on uterine leiomyomas in postmenopausal women. Fertil Steril 2005;84:154-161. (Pubitemid 40991475)
47. Wei J, Chiriboga L, Mizuguchi M, Yee H, Mittal K. Expression profle of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata. Mod Pathol 2005;18:179-188. (Pubitemid 40188624)
48. Kayisli UA, Berkkanoglu M, Kizilay G, Senturk L, Arici A. Expression of proliferative and preapoptotic molecules in human myometrium and leiomyoma throughout the menstrual cycle. Reprod Sci 2007;14:678-686. (Pubitemid 351903570)
49. Kovács KA, Lengyel F, Vértes Z, Környei JL, Gocze PM, Sumegi B, Szabó I, Vértes M. Phosphorylation of PTEN (phosphatase and tensin homologue deleted on chromosome ten) protein is enhanced in human fbromyomatous uteri. J Steroid Biochem Mol Biol 2007;103:196-199. (Pubitemid 46149303)
50. Peng L, Wen Y, Han Y, Wei A, Shi G, Mizuguchi M, Lee P, et al. Expression of insulin-like growth factors (IGFs) and IGF signaling: molecular complexity in uterine leiomyomas. Fertil Steril 2009;91:2664-2675.
51. Karra L, Shushan A, Ben-Meir A, Rojansky N, Klein BY, Shveiky D, Levitzki R, Ben-Bassat H. Changes related to phosphatidylinositol 3-kinase/Akt signaling in leiomyomas: possible involvement of glycogen synthase kinase 3alpha and cyclin D2 in the pathophysiology. Fertil Steril 2010;93:2646-2651.
52. Crabtree JS, Jelinsky SA, Harris HA, Choe SE, Cotreau MM, Kimberland ML, Wilson E, et al. Comparison of human and rat uterine leiomyomata: identifcation of a dysregulated mammalian target of rapamycin pathway. Cancer Res 2009;69:6171-6178.
53. Hoekstra AV, Sefon EC, Berry E, Lu Z, Hardt J, Marsh E, Yin P, et al. Progestins activate the AKT pathway in leiomyoma cells and promote survival. J Clin Endocrinol Metab 2009;94:1768-1774.
54. Laudanski P, Szamatowicz J, Kowalczuk O, Kuzmicki M, Grabowicz M, Chyczewski L. Expression of selected tumor suppressor and oncogenes in endometrium of women with endometriosis. Hum Reprod 2009;24:1880-1890.
55. Matsuzaki S, Murakami T, Uehara S, Canis M, Sasano H, Okamura K. Expression of estrogen receptor alpha and beta in peritoneal and ovarian endometriosis. Fertil Steril 2001;75:1198-1205. (Pubitemid 32522620)
56. Honda H, Barrueto FF, Gogusev J, Im DD, Morin PJ. Serial analysis of gene expression reveals diferential expression between endometriosis and normal endometrium. Possible roles for AXL and SHC1 in the pathogenesis of endometriosis. Reprod Biol Endocrinol 2008;6:59.
57. Zhang H, Zhao X, Liu S, Li J, Wen Z, Li M. 17betaE2 promotes cell proliferation in endometriosis by decreasing PTEN via NFkappaB-dependent pathway. Mol Cell Endocrinol 2010;317:31-43.
58. Yoshino O, Osuga Y, Hirota Y, Koga K, Hirata T, Harada M, Morimoto C, et al. Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis. Am J Reprod Immunol 2004;52:306-311. (Pubitemid 39585717)
59. Banu SK, Lee J, Speights VO Jr, Starzinski-Powitz A, Arosh JA. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms. Mol Endocrinol 2009;23:1291-1305.
60. Yoshino O, Osuga Y, Koga K, Hirota Y, Hirata T, Ruimeng X, Na L, et al. FR 167653, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis in a murine model. J Reprod Immunol 2006;72:85-93. (Pubitemid 44711877)
61. Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 2007;148:3814-3826. (Pubitemid 47105847)
62. Velarde MC, Aghajanova L, Nezhat CR, Giudice LC. Increased mitogen-activated protein kinase kinase/extracellularly regulated kinase activity in human endometrial stromal fbroblasts of women with endometriosis reduces 3′,5′-cyclic adenosine 5′-monophosphate inhibition of cyclin D1. Endocrinology 2009;150:4701-4712.
63. Ngô C, Chéreau C, Nicco C, Weill B, Chapron C, Batteux F. Reactive oxygen species controls endometriosis progression. Am J Pathol 2009;175:225-234.
64. Wu Y, Kajdacsy-Balla A, Strawn E, Basir Z, Halverson G, Jailwala P, Wang Y, et al. Transcriptional characterizations of differences between eutopic and ectopic endometrium. Endocrinology 2006;147:232-246. (Pubitemid 43004277)
65. Cinar O, Seval Y, Uz YH, Cakmak H, Ulukus M, Kayisli UA, Arici A. Diferential regulation of Akt phosphorylation in endometriosis. Reprod Biomed Online 2009;19:864-871.
66. Zhang H, Li M, Zheng X, Sun Y, Wen Z, Zhao X. Endometriotic stromal cells lose the ability to regulate cell-survival signaling in endometrial epithelial cells in vitro. Mol Hum Reprod 2009;15:653-663.
67. Yagyu T, Tsuji Y, Haruta S, Kitanaka T, Yamada Y, Kawaguchi R, Kanayama S, et al. Activation of mammalian target of rapamycin in postmenopausal ovarian endometriosis. Int J Gynecol Cancer 2006;16:1545-1551. (Pubitemid 44060377)
68. Hsieh YY, Wang YK, Chang CC, Lin CS. Estrogen receptor alpha-351 XbaI*G and-397 PvuII*C-related genotypes and alleles are associated with higher susceptibilities of endometriosis and leiomyoma. Mol Hum Reprod 2007;13:117-122.
69. Govindan S, Shaik NA, Vedicherla B, Kodati V, Rao K P, Hasan Q. Estrogen receptor-alpha gene (T/C) Pvu II polymorphism in endometriosis and uterine fbroids. Dis Markers 2009;26:149-154.
70. Wise LA, Palmer JR, Stewart EA, Rosenberg L. Polycystic ovary syndrome and risk of uterine leiomyomata. Fertil Steril 2007;87:1108-1115. (Pubitemid 46659943)