钠氢交换蛋白1与肿瘤耐药
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摘要
化疗药物耐药逐渐成为肿瘤治疗的主要障碍。肿瘤耐药的发生机制主要包括药物的外排增加、DNA修复增强、凋亡受抑、上皮-间质转化以及肿瘤干细胞的存在。因此,迫切需要寻找新的生物标志物,通过逆转肿瘤的耐药性,从而增加化疗药物的疗效,以提高患者的总体生存率。钠氢交换蛋白(sodium-hydrogen exchanger 1, NHE1)在调控肿瘤细胞的增殖、凋亡和耐药中发挥重要作用,被认为是肿瘤治疗中调控耐药性的潜在靶标。本文简要介绍钠氢交换蛋白的结构和主要功能,重点阐述钠氢交换蛋白对肿瘤耐药的影响和调控机制,以及在肿瘤的发展、转移中的作用的研究进展。
Chemotherapeutic drug resistance has gradually become a major obstacle to clinical cancer treatment. The mechanisms of tumor resistance include increased drug efflux, enhanced DNA repair, inhibition of apoptosis, epithelial-mesenchymal transformation, and emerging of cancer stem cells. Therefore, it is urgent to find new biomarkers to increase the efficacy of chemotherapeutical drugs and improve the overall survival rate by reversing the development of tumor resistance. Sodium-hydrogen exchanger 1(NHE1) plays an important role in the regulation of tumor cell proliferation, apoptosis, and drug resistance, which can be considered as one of the potential targets for drug resistance in cancer treatments. In this paper, we briefly introduce the structure and main functions of NHE1, and review the effects and regulatory mechanisms of NHE1 on tumor resistance, as well as the role of NHE1 in the development and metastasis of cancer.
Chemotherapeutic drug resistance has gradually become a major obstacle to clinical cancer treatment. The mechanisms of tumor resistance include increased drug efflux, enhanced DNA repair, inhibition of apoptosis, epithelial-mesenchymal transformation, and emerging of cancer stem cells. Therefore, it is urgent to find new biomarkers to increase the efficacy of chemotherapeutical drugs and improve the overall survival rate by reversing the development of tumor resistance. Sodium-hydrogen exchanger 1(NHE1) plays an important role in the regulation of tumor cell proliferation, apoptosis, and drug resistance, which can be considered as one of the potential targets for drug resistance in cancer treatments. In this paper, we briefly introduce the structure and main functions of NHE1, and review the effects and regulatory mechanisms of NHE1 on tumor resistance, as well as the role of NHE1 in the development and metastasis of cancer.
引文
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[7] 陈琦, 冯凡, 朱小兰, 等. 钠氢交换蛋白抑制剂Cariporide对MCF-7/ADR细胞化疗敏感性影响机制[J]. 中华肿瘤防治杂志(Chen Q, Feng F, Zhu XL, et al. Mechanism of NHE1 inhibitor on the sensitivity of MCF-7/ADR cells to chemotherapeutic drug resistance[J]. Chin J Cancer Prev Treat), 2017, 24(8): 512-517
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[9] Li X, Khan MF, Schriemer DC, et al. Structural changes in the C-terminal regulatory region of the Na+/H+ exchanger mediate phosphorylation induced regulation[J]. J Mol Cell Cardiol, 2013, 61: 153-163
[10] Li T, Yi L, Hai L, et al. The interactome and spatial redistribution feature of Ca2+ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion[J]. Cell Death Dis, 2018, 9(3): 292
[11] Cottle W, Wallert M, Provost J. Impact of calcineurin homologous protein and NHE1 on lung cancer cell Adaptation to Hypoxia and Serum Deprivation[J]. Transportation, 2012, 39(5).doi:10.1007/s11116-011- 9379-0
[12] Zhang S, Liu F, Mao X, et al. Elevation of miR-27b by HPV16 E7 inhibits PPARgamma expression and promotes proliferation and invasion in cervical carcinoma cells[J]. Int J Oncol, 2015, 47(5): 1759-1766
[13] Chang HR, Lien CF, Jeng JR, et al. Intermittent hypoxia inhibits Na+-H+ exchange-mediated acid extrusion via Intracellular Na+ accumulation in cardiomyocytes[J]. Cell Physiol Biochem, 2018, 46(3): 1252-1262
[14] Yeves AM, Burgos JI, Medina AJ, et al. Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE-1 activity[J]. Acta Physiol (Oxf), 2018: e13092
[15] Hendus-Altenburger R, Lambrughi M, Terkelsen T, et al. A phosphorylation-motif for tuneable helix stabilisation in intrinsically disordered proteins - Lessons from the sodium proton exchanger 1 (NHE1)[J]. Cell Signal, 2017, 37: 40-51
[16] Amith SR, Fliegel L. Na+/H+ exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics[J]. Semin Cancer Biol, 2017, 43: 35-41
[17] Andersen AP, Samsoe-Petersen J, Oernbo EK, et al. The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms[J]. Int J Cancer, 2018, 142(12): 2529-2542
[18] Zhu W, Carney KE, Pigott VM, et al. Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1[J]. Carcinogenesis, 2016, 37(9): 839-851
[19] Altaf E, Huang X, Xiong J, et al. NHE1 has a notable role in metastasis and drug resistance of T-cell acute lymphoblastic leukemia[J]. Oncol Lett, 2017, 14(4): 4256-4262
[20] Pedersen AK, Mendes Lopes de Melo J, Morup N, et al. Tumor microenvironment conditions alter Akt and Na+/H+ exchanger NHE1 expression in endothelial cells more than hypoxia alone: implications for endothelial cell function in cancer[J]. BMC Cancer, 2017, 17(1): 542
[21] Cho S, Lu M, He X, et al. Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells[J]. Proc Natl Acad Sci U S A, 2011, 108(51): 20778-20783
[22] Amith SR, Wilkinson JM, Baksh S, et al. The Na+/H+ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells[J]. Oncotarget, 2015, 6(2): 1262-1275
[23] 任新华, 王卫平. 细胞自噬在肿瘤化疗耐药中的作用[J]. 中国生物化学与分子生物学报(Ren XH, Wang WP. Role of autophagy in cancer chemoresistance[J]. Chin J Biochem Mol Biol), 2015, 31(5): 448-454
[24] Shi H, Zhao X, Ding Z, et al. Na+/H+ Exchanger Regulates Amino Acid-Mediated Autophagy in Intestinal Epithelial Cells[J]. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol, 2017, 42(6): 2418-2429
[25] Aredia F, Czaplinski S, Fulda S, et al. Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage[J]. BMC Cancer, 2016, 16(1): 851
[26] Yu M, Lee C, Wang M, et al. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors[J]. Cancer Sci, 2015, 106(10): 1438-1447
[27] Ma D, Fang Q, Wang P, et al. Induction of heme oxygenase-1 by Na+-H+ exchanger 1 protein plays a crucial role in imatinib-resistant chronic myeloid leukemia cells[J].J Biol Chem,2015,290(20):12558-12571
[28] Chen L, Cong D, Li Y, et al. Combination of sonodynamic with temozolomide inhibits C6 glioma migration and promotes mitochondrial pathway apoptosis via suppressing NHE-1 expression[J]. Ultrason Sonochem, 2017, 39: 654-661
[29] Monet M, Poet M, Tauzin S, et al. The cleaved FAS ligand activates the Na+/H+ exchanger NHE1 through Akt/ROCK1 to stimulate cell motility[J]. Sci Rep, 2016, 6: 28008
[30] Zhao Y, Cui G, Zhang N, et al. Lipopolysaccharide induces endothelial cell apoptosis via activation of Na+/H+ exchanger 1 and calpain-dependent degradation of Bcl-2[J]. Biochem Biophys Res Commun, 2012, 427(1): 125-132
[31] Sigurethsson HH, Olesen CW, Dybboe R, et al. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms[J]. Mol Cancer Res, 2015, 13(1): 63-77
[32] Avnet S, Lemma S, Cortini M, et al. Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance[J]. Oncotarget, 2016, 7(39): 63408-63423
[33] Alfarouk KO, Stock CM, Taylor S, et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp[J]. Cancer Cell Int, 2015, 15: 71
[34] Oba T, Izumi H, Ito KI. ABCB1 and ABCC11 confer resistance to eribulin in breast cancer cell lines[J]. Oncotarget, 2016, 7(43): 70011-70027
[35] Daniel C, Bell C, Burton C, et al. The role of proton dynamics in the development and maintenance of multidrug resistance in cancer[J]. Biochim Biophys Acta, 2013, 1832(5): 606-617
[36] Shi Q, Zhang L, Liu M, et al. Reversion of multidrug resistance by a pH-responsive cyclodextrin-derived nanomedicine in drug resistant cancer cells[J]. Biomaterials, 2015, 67: 169-182
[37] Jin W, Li Q, Lin Y, et al. Reversal of Imatinib resistance in BCR-ABL-positive leukemia after inhibition of the Na+/H+ exchanger[J]. Cancer Lett, 2011, 308(1): 81-90
[38] Jin W, Lu Y, Li Q, et al. Down-regulation of the P-glycoprotein relevant for multidrug resistance by intracellular acidification through the crosstalk of MAPK signaling pathways[J]. Int J Biochem Cell Biol, 2014, 54: 111-121
[39] Gao W, Zhang H, Chang G, et al. Decreased intracellular pH induced by cariporide differentially contributes to human umbilical cord-derived mesenchymal stem cells differentiation[J]. Cell Physiol Biochem, 2014, 33(1): 185-194
[40] Li P, Yang R, Gao WQ. Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer[J]. Mol Cancer, 2014, 13: 55
[2] Parks SK, Chiche J, Pouyssegur J. Disrupting proton dynamics and energy metabolism for cancer therapy[J]. Nat Rev Cancer, 2013, 13(9): 611-623
[3] Andersen AP, Flinck M, Oernbo EK, et al. Roles of acid-extruding ion transporters in regulation of breast cancer cell growth in a 3-dimensional microenvironment[J]. Mol Cancer, 2016, 15(1): 45
[4] Granja S, Tavares-Valente D, Queiros O, et al. Value of pH regulators in the diagnosis, prognosis and treatment of cancer[J]. Semin Cancer Biol, 2017, 43: 17-34
[5] Reshkin SJ, Greco MR, Cardone RA. Role of pHi, and proton transporters in oncogene-driven neoplastic transformation[J]. Philos Trans R Soc Lond B Biol Sci, 2014, 369(1638): 20130100
[6] Gottesman MM, Pastan IH. The role of multidrug resistance efflux pumps in cancer: revisiting a JNCI publication exploring expression of the MDR1 (P-glycoprotein) gene[J]. J Natl Cancer Inst, 2015, 107(9). pii:djv222
[7] 陈琦, 冯凡, 朱小兰, 等. 钠氢交换蛋白抑制剂Cariporide对MCF-7/ADR细胞化疗敏感性影响机制[J]. 中华肿瘤防治杂志(Chen Q, Feng F, Zhu XL, et al. Mechanism of NHE1 inhibitor on the sensitivity of MCF-7/ADR cells to chemotherapeutic drug resistance[J]. Chin J Cancer Prev Treat), 2017, 24(8): 512-517
[8] Amith SR, Fliegel L. Regulation of the Na+/H+ exchanger (NHE1) in breast cancer metastasis[J]. Cancer Res, 2013, 73(4): 1259-1264
[9] Li X, Khan MF, Schriemer DC, et al. Structural changes in the C-terminal regulatory region of the Na+/H+ exchanger mediate phosphorylation induced regulation[J]. J Mol Cell Cardiol, 2013, 61: 153-163
[10] Li T, Yi L, Hai L, et al. The interactome and spatial redistribution feature of Ca2+ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion[J]. Cell Death Dis, 2018, 9(3): 292
[11] Cottle W, Wallert M, Provost J. Impact of calcineurin homologous protein and NHE1 on lung cancer cell Adaptation to Hypoxia and Serum Deprivation[J]. Transportation, 2012, 39(5).doi:10.1007/s11116-011- 9379-0
[12] Zhang S, Liu F, Mao X, et al. Elevation of miR-27b by HPV16 E7 inhibits PPARgamma expression and promotes proliferation and invasion in cervical carcinoma cells[J]. Int J Oncol, 2015, 47(5): 1759-1766
[13] Chang HR, Lien CF, Jeng JR, et al. Intermittent hypoxia inhibits Na+-H+ exchange-mediated acid extrusion via Intracellular Na+ accumulation in cardiomyocytes[J]. Cell Physiol Biochem, 2018, 46(3): 1252-1262
[14] Yeves AM, Burgos JI, Medina AJ, et al. Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE-1 activity[J]. Acta Physiol (Oxf), 2018: e13092
[15] Hendus-Altenburger R, Lambrughi M, Terkelsen T, et al. A phosphorylation-motif for tuneable helix stabilisation in intrinsically disordered proteins - Lessons from the sodium proton exchanger 1 (NHE1)[J]. Cell Signal, 2017, 37: 40-51
[16] Amith SR, Fliegel L. Na+/H+ exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics[J]. Semin Cancer Biol, 2017, 43: 35-41
[17] Andersen AP, Samsoe-Petersen J, Oernbo EK, et al. The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms[J]. Int J Cancer, 2018, 142(12): 2529-2542
[18] Zhu W, Carney KE, Pigott VM, et al. Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1[J]. Carcinogenesis, 2016, 37(9): 839-851
[19] Altaf E, Huang X, Xiong J, et al. NHE1 has a notable role in metastasis and drug resistance of T-cell acute lymphoblastic leukemia[J]. Oncol Lett, 2017, 14(4): 4256-4262
[20] Pedersen AK, Mendes Lopes de Melo J, Morup N, et al. Tumor microenvironment conditions alter Akt and Na+/H+ exchanger NHE1 expression in endothelial cells more than hypoxia alone: implications for endothelial cell function in cancer[J]. BMC Cancer, 2017, 17(1): 542
[21] Cho S, Lu M, He X, et al. Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells[J]. Proc Natl Acad Sci U S A, 2011, 108(51): 20778-20783
[22] Amith SR, Wilkinson JM, Baksh S, et al. The Na+/H+ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells[J]. Oncotarget, 2015, 6(2): 1262-1275
[23] 任新华, 王卫平. 细胞自噬在肿瘤化疗耐药中的作用[J]. 中国生物化学与分子生物学报(Ren XH, Wang WP. Role of autophagy in cancer chemoresistance[J]. Chin J Biochem Mol Biol), 2015, 31(5): 448-454
[24] Shi H, Zhao X, Ding Z, et al. Na+/H+ Exchanger Regulates Amino Acid-Mediated Autophagy in Intestinal Epithelial Cells[J]. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol, 2017, 42(6): 2418-2429
[25] Aredia F, Czaplinski S, Fulda S, et al. Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage[J]. BMC Cancer, 2016, 16(1): 851
[26] Yu M, Lee C, Wang M, et al. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors[J]. Cancer Sci, 2015, 106(10): 1438-1447
[27] Ma D, Fang Q, Wang P, et al. Induction of heme oxygenase-1 by Na+-H+ exchanger 1 protein plays a crucial role in imatinib-resistant chronic myeloid leukemia cells[J].J Biol Chem,2015,290(20):12558-12571
[28] Chen L, Cong D, Li Y, et al. Combination of sonodynamic with temozolomide inhibits C6 glioma migration and promotes mitochondrial pathway apoptosis via suppressing NHE-1 expression[J]. Ultrason Sonochem, 2017, 39: 654-661
[29] Monet M, Poet M, Tauzin S, et al. The cleaved FAS ligand activates the Na+/H+ exchanger NHE1 through Akt/ROCK1 to stimulate cell motility[J]. Sci Rep, 2016, 6: 28008
[30] Zhao Y, Cui G, Zhang N, et al. Lipopolysaccharide induces endothelial cell apoptosis via activation of Na+/H+ exchanger 1 and calpain-dependent degradation of Bcl-2[J]. Biochem Biophys Res Commun, 2012, 427(1): 125-132
[31] Sigurethsson HH, Olesen CW, Dybboe R, et al. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms[J]. Mol Cancer Res, 2015, 13(1): 63-77
[32] Avnet S, Lemma S, Cortini M, et al. Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance[J]. Oncotarget, 2016, 7(39): 63408-63423
[33] Alfarouk KO, Stock CM, Taylor S, et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp[J]. Cancer Cell Int, 2015, 15: 71
[34] Oba T, Izumi H, Ito KI. ABCB1 and ABCC11 confer resistance to eribulin in breast cancer cell lines[J]. Oncotarget, 2016, 7(43): 70011-70027
[35] Daniel C, Bell C, Burton C, et al. The role of proton dynamics in the development and maintenance of multidrug resistance in cancer[J]. Biochim Biophys Acta, 2013, 1832(5): 606-617
[36] Shi Q, Zhang L, Liu M, et al. Reversion of multidrug resistance by a pH-responsive cyclodextrin-derived nanomedicine in drug resistant cancer cells[J]. Biomaterials, 2015, 67: 169-182
[37] Jin W, Li Q, Lin Y, et al. Reversal of Imatinib resistance in BCR-ABL-positive leukemia after inhibition of the Na+/H+ exchanger[J]. Cancer Lett, 2011, 308(1): 81-90
[38] Jin W, Lu Y, Li Q, et al. Down-regulation of the P-glycoprotein relevant for multidrug resistance by intracellular acidification through the crosstalk of MAPK signaling pathways[J]. Int J Biochem Cell Biol, 2014, 54: 111-121
[39] Gao W, Zhang H, Chang G, et al. Decreased intracellular pH induced by cariporide differentially contributes to human umbilical cord-derived mesenchymal stem cells differentiation[J]. Cell Physiol Biochem, 2014, 33(1): 185-194
[40] Li P, Yang R, Gao WQ. Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer[J]. Mol Cancer, 2014, 13: 55