LKB1-AMPK-mTOR信号通路在子宫内膜癌的研究现状
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摘要
子宫内膜癌(EC)为女性生殖系统3大恶性肿瘤之一,其病因迄今尚未阐明。肝激酶B1(LKB1),又被称为丝氨酸/苏氨酸激酶(STK)11,是肿瘤抑制激酶。在波伊茨-耶格综合征(PJS)患者中,LKB1失去活性。LKB1磷酸化、磷酸AMP活化蛋白激酶(AMPK)激活及哺乳动物西罗莫司靶蛋白(mTOR)抑制,均可抑制包括EC在内的肿瘤细胞增殖及其能量代谢。EC的发生和发展与LKB1-AMPK-mTOR信号通路密切相关。笔者拟阐述LKB1-AMPK-mTOR信号通路对于EC作用的研究现状,以及通过该信号通路治疗EC的最新研究进展。
Endometrial cancer(EC) is one of the three major malignant tumors of the female reproductive system, and its etiology has not yet been elucidated. Liver kinase B1(LKB1), also known as serine/threonine kinase(STK)11, is a tumor suppressor kinase. In patients with Peutz-Jeghers syndrome(PJS), LKB1 loses activity. LKB1 phosphorylation, activation of phospho-AMP-activated protein kinase(AMPK) and inhibition of mammalian target of rapamycin(mTOR) can inhibit tumor cell proliferation and energy metabolism, including the development of EC. The occurrence and development of EC is closely related to the LKB1-AMPK-mTOR signaling pathway. The article focuses on expounding the current research status of LKB1-AMPK-mTOR signaling pathway on EC, and outlining the latest research progress in the treatment of EC through this signaling pathway.
Endometrial cancer(EC) is one of the three major malignant tumors of the female reproductive system, and its etiology has not yet been elucidated. Liver kinase B1(LKB1), also known as serine/threonine kinase(STK)11, is a tumor suppressor kinase. In patients with Peutz-Jeghers syndrome(PJS), LKB1 loses activity. LKB1 phosphorylation, activation of phospho-AMP-activated protein kinase(AMPK) and inhibition of mammalian target of rapamycin(mTOR) can inhibit tumor cell proliferation and energy metabolism, including the development of EC. The occurrence and development of EC is closely related to the LKB1-AMPK-mTOR signaling pathway. The article focuses on expounding the current research status of LKB1-AMPK-mTOR signaling pathway on EC, and outlining the latest research progress in the treatment of EC through this signaling pathway.
引文
[1] Lortet-Tieulent J, Ferlay J, Bray F, et al. International patterns and trends in endometrial cancer incidence, 1978-2013[J]. J Natl Cancer Inst, 2018, 110(4): 354-361.
[2] 王丽红, 郭春燕, 瞿全新. LKB1/AMPK/mTOR信号转导通路在子宫内膜癌发病机制中的研究[J]. 中国妇幼保健, 2014, 29(12): 1933-1936.
[3] Resta N, Pierannunzio D, Lenato GM, et al. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study[J]. Digest Liver Dis, 2013, 45(7): 606-611.
[4] Veleva-Rotse BO, Smart JL, Baas AF, et al. STRAD pseudokinases regulate axogenesis and LKB1 stability[J]. Neural Dev, 2014, 9(1): 5.
[5] Konena J, Wilkinsona S, Leec B, et al. LKB1 kinase-dependent and independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion[J]. Mol Biol Cell, 2016, 27(7): 1069-1084.
[6] Dogliotti G, Kullmann L, Dhumale P, et al. Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression[J]. Nat Commun, 2017, 8: 15747.
[7] Fogarty S, Ross FA, Vara Ciruelos D, et al. AMPK causes cell cycle arrest in LKB1-deficient cells via activation of CAMKK2[J]. Mol Cancer Res, 2016, 14 (8): 683-695.
[8] Hardie DG, Lin SC. AMP-activated protein kinase not just an energy sensor[J]. F1000Res, 2017, 6: 1724.
[9] Li XD, Wang LL, Zhou XE, et al. Structural basis of AMPK regulation by adenine nucleotides and glycogen[J]. Cell Res, 2015, 25(1): 50-66.
[10] Faubert B, Boily G, Izreig S, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo[J]. Cell Metab, 2013, 17(1): 113-124.
[11] Duan P, Hu CH, Quan C, et al. 4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in sertoli cells[J]. Toxicol Lett, 2017, 267(1): 21-31.
[12] Brockhoff M, Rion N, Chojnowska K, et al. Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy typeⅠ[J]. J Clin Invest, 2017, 127(2): 549-563.
[13] Bian YH, Xu J, Zhao WY, et al. Targeting mTORC2 component rictor inhibits cell proliferation and promotes apoptosis in gastric cancer[J]. Am J Transl Res, 2017, 9(9): 4317-4330.
[14] Gailite I, Aerne BL, Tapon N. Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system[J]. Proc Natl Acad Sci USA, 2015, 112(37): E5169-E5178.
[15] Sun D, Liu H, Dai X, et al. Aspirin disrupts the mTOR-raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition[J]. Cancer Lett, 2017, 406: 105-115.
[16] Howell JJ, Hellberg K, Turner M, et al. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex[J]. Cell Metab, 2017, 25(2): 463-471.
[17] Yuan Y, Xue X, Guo RB, et al. Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway[J]. CNS Neurosci Ther, 2012, 18(7): 536-546.
[18] Hsu JL, Liu SP, Lee CC, et al. A unique amidoanthraquinone derivative displays antiproliferative activity against human hormone-refractory metastatic prostate cancers through activation of LKB1-AMPK-mTOR signaling pathway[J]. Naunyn Schmiedebergs Arch Pharmacol, 2014, 387(10): 979-990.
[19] Nead KT, Sharp SJ, Thompson DJ, et al. Evidence of a causal association between insulinemia and endometrial cancer: a mendelian randomization analysis[J]. J Nat Cancer Inst, 2015, 107(9): 1-7.
[20] Jian J, Hanab L, Zhangbcd HG, et al. Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling[J]. Gynecol Oncol, 2015, 138(3): 668-675.
[21] Zhang Y, Xu F, Liang H, et al. Exenatide inhibits the growth of endometrial cancer Ishikawa xenografts in nude mice[J]. Oncol Rep, 2016, 35(3): 1340-1348.
[22] Yang F, Zhang L, Gao Z, et al. Exogenous H2S protects against diabetic cardiomyopathy by activating autophagy via the AMPK/mTOR pathway[J]. Cell Physiol Biochem, 2017, 43(3): 1168-1187.
[23] Yin H, Zhao L, Li S, et al. Impaired cellular energy metabolism contributes to duck-enteritis-virus-induced autophagy via the AMPK-TSC2-MTOR signaling pathway[J]. Front Cell Infect Microbiol, 2017, 7: 423.
[24] Song Y, Zhang P, Sun Y, et al. AMPK activation-dependent autophagy compromises oleanolic acid-induced cytotoxicity in human bladder cancer cells[J]. Oncotarget, 2017, 8(40): 67942-67954.
[25] Kanda R, Hiraike H, Wada-Hiraike O, et al. Expression of the glucagon-like peptide-1 receptor and its role in regulating autophagy in endometrial cancer[J]. BMC Cancer, 2018,18(1): 657.
[26] Ikeda Y, Kiyotani K, Yew PY, et al. Clinical significance of T cell clonality and expression levels of immune-related genes in endometrial cancer[J]. Oncol Rep, 2017, 37(5): 2603-2610.
[27] Peňa CG, Nakada Y, Saatcioglu HD, et al. LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment[J]. J Clin Invest, 2015, 125(11): 4063-4076.
[28] Lee S, Lee E, Ko E, et al. Tumor-associated macrophages secrete CCL2 and induce the invasive phenotype of human breast epithelial cells through upregulation of ERO1-α and MMP-9[J]. Cancer Lett, 2018, 437(1): 25-34.
[29] Gallos ID, Yap J, Rajkhowa M, et al. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis[J]. Am J Obstet Gynecol, 2012, 207(4): 266.e1-e266.e12.
[30] Akira M, Takako K, Yasunori S, et al. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial[J]. Cancer, 2014, 120(19): 2986-2995.
[31] Gu CJ, Cheng J, Zhang B, et al. Protopanaxadiol and metformin synergistically inhibit estrogen-mediated proliferation and anti-autophagy effects in endometrial cancer cells[J]. Am J Transl Res, 2017, 9(9): 4071-4082.
[32] Oh J, Kim GD, Kim S, et al. Antofine, a natural phenanthroindolizidine alkaloid, suppresses angiogenesis via regulation of AKT/mTOR and AMPK pathway in endothelial cells and endothelial progenitor cells derived from mouse embryonic stem cells[J]. Food Chem Toxicol, 2017, 107(Pt A): 201-207.
[33] Slomovitz BM, Lu KH, Johnston T, et al. A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma[J]. Cancer, 2010, 116(23): 5415-5149.
[34] Contreras CM, Akbay EA, Gallardo TD, et al. Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy[J]. Dis Model Mech, 2010, 3(3-4): 181-193.
[35] Lu KH, Wu W, Dave B, et al. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma[J]. Clin Cancer Res, 2008, 14(9): 2543-2550.
[2] 王丽红, 郭春燕, 瞿全新. LKB1/AMPK/mTOR信号转导通路在子宫内膜癌发病机制中的研究[J]. 中国妇幼保健, 2014, 29(12): 1933-1936.
[3] Resta N, Pierannunzio D, Lenato GM, et al. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study[J]. Digest Liver Dis, 2013, 45(7): 606-611.
[4] Veleva-Rotse BO, Smart JL, Baas AF, et al. STRAD pseudokinases regulate axogenesis and LKB1 stability[J]. Neural Dev, 2014, 9(1): 5.
[5] Konena J, Wilkinsona S, Leec B, et al. LKB1 kinase-dependent and independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion[J]. Mol Biol Cell, 2016, 27(7): 1069-1084.
[6] Dogliotti G, Kullmann L, Dhumale P, et al. Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression[J]. Nat Commun, 2017, 8: 15747.
[7] Fogarty S, Ross FA, Vara Ciruelos D, et al. AMPK causes cell cycle arrest in LKB1-deficient cells via activation of CAMKK2[J]. Mol Cancer Res, 2016, 14 (8): 683-695.
[8] Hardie DG, Lin SC. AMP-activated protein kinase not just an energy sensor[J]. F1000Res, 2017, 6: 1724.
[9] Li XD, Wang LL, Zhou XE, et al. Structural basis of AMPK regulation by adenine nucleotides and glycogen[J]. Cell Res, 2015, 25(1): 50-66.
[10] Faubert B, Boily G, Izreig S, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo[J]. Cell Metab, 2013, 17(1): 113-124.
[11] Duan P, Hu CH, Quan C, et al. 4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in sertoli cells[J]. Toxicol Lett, 2017, 267(1): 21-31.
[12] Brockhoff M, Rion N, Chojnowska K, et al. Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy typeⅠ[J]. J Clin Invest, 2017, 127(2): 549-563.
[13] Bian YH, Xu J, Zhao WY, et al. Targeting mTORC2 component rictor inhibits cell proliferation and promotes apoptosis in gastric cancer[J]. Am J Transl Res, 2017, 9(9): 4317-4330.
[14] Gailite I, Aerne BL, Tapon N. Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system[J]. Proc Natl Acad Sci USA, 2015, 112(37): E5169-E5178.
[15] Sun D, Liu H, Dai X, et al. Aspirin disrupts the mTOR-raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition[J]. Cancer Lett, 2017, 406: 105-115.
[16] Howell JJ, Hellberg K, Turner M, et al. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex[J]. Cell Metab, 2017, 25(2): 463-471.
[17] Yuan Y, Xue X, Guo RB, et al. Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway[J]. CNS Neurosci Ther, 2012, 18(7): 536-546.
[18] Hsu JL, Liu SP, Lee CC, et al. A unique amidoanthraquinone derivative displays antiproliferative activity against human hormone-refractory metastatic prostate cancers through activation of LKB1-AMPK-mTOR signaling pathway[J]. Naunyn Schmiedebergs Arch Pharmacol, 2014, 387(10): 979-990.
[19] Nead KT, Sharp SJ, Thompson DJ, et al. Evidence of a causal association between insulinemia and endometrial cancer: a mendelian randomization analysis[J]. J Nat Cancer Inst, 2015, 107(9): 1-7.
[20] Jian J, Hanab L, Zhangbcd HG, et al. Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling[J]. Gynecol Oncol, 2015, 138(3): 668-675.
[21] Zhang Y, Xu F, Liang H, et al. Exenatide inhibits the growth of endometrial cancer Ishikawa xenografts in nude mice[J]. Oncol Rep, 2016, 35(3): 1340-1348.
[22] Yang F, Zhang L, Gao Z, et al. Exogenous H2S protects against diabetic cardiomyopathy by activating autophagy via the AMPK/mTOR pathway[J]. Cell Physiol Biochem, 2017, 43(3): 1168-1187.
[23] Yin H, Zhao L, Li S, et al. Impaired cellular energy metabolism contributes to duck-enteritis-virus-induced autophagy via the AMPK-TSC2-MTOR signaling pathway[J]. Front Cell Infect Microbiol, 2017, 7: 423.
[24] Song Y, Zhang P, Sun Y, et al. AMPK activation-dependent autophagy compromises oleanolic acid-induced cytotoxicity in human bladder cancer cells[J]. Oncotarget, 2017, 8(40): 67942-67954.
[25] Kanda R, Hiraike H, Wada-Hiraike O, et al. Expression of the glucagon-like peptide-1 receptor and its role in regulating autophagy in endometrial cancer[J]. BMC Cancer, 2018,18(1): 657.
[26] Ikeda Y, Kiyotani K, Yew PY, et al. Clinical significance of T cell clonality and expression levels of immune-related genes in endometrial cancer[J]. Oncol Rep, 2017, 37(5): 2603-2610.
[27] Peňa CG, Nakada Y, Saatcioglu HD, et al. LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment[J]. J Clin Invest, 2015, 125(11): 4063-4076.
[28] Lee S, Lee E, Ko E, et al. Tumor-associated macrophages secrete CCL2 and induce the invasive phenotype of human breast epithelial cells through upregulation of ERO1-α and MMP-9[J]. Cancer Lett, 2018, 437(1): 25-34.
[29] Gallos ID, Yap J, Rajkhowa M, et al. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis[J]. Am J Obstet Gynecol, 2012, 207(4): 266.e1-e266.e12.
[30] Akira M, Takako K, Yasunori S, et al. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial[J]. Cancer, 2014, 120(19): 2986-2995.
[31] Gu CJ, Cheng J, Zhang B, et al. Protopanaxadiol and metformin synergistically inhibit estrogen-mediated proliferation and anti-autophagy effects in endometrial cancer cells[J]. Am J Transl Res, 2017, 9(9): 4071-4082.
[32] Oh J, Kim GD, Kim S, et al. Antofine, a natural phenanthroindolizidine alkaloid, suppresses angiogenesis via regulation of AKT/mTOR and AMPK pathway in endothelial cells and endothelial progenitor cells derived from mouse embryonic stem cells[J]. Food Chem Toxicol, 2017, 107(Pt A): 201-207.
[33] Slomovitz BM, Lu KH, Johnston T, et al. A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma[J]. Cancer, 2010, 116(23): 5415-5149.
[34] Contreras CM, Akbay EA, Gallardo TD, et al. Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy[J]. Dis Model Mech, 2010, 3(3-4): 181-193.
[35] Lu KH, Wu W, Dave B, et al. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma[J]. Clin Cancer Res, 2008, 14(9): 2543-2550.