Inhibition of TRPM7 suppresses migration and invasion of prostate cancer cells via inactivation of ERK1/2, Src and Akt pathway signaling
1Joint Institute for Regenerative Medicine, Kyungpook National University, 41571 Daegu, Republic of Korea
2Department of Urology, School of Medicine, Kyungpook National University, 41571 Daegu, Republic of Korea
3Department of Urology, School of Medicine, Kyungpook National University Chilgok Hospital, 41944 Daegu, Republic of Korea
4Department of Brain and Cognitive Sciences, Core Protein Resources Center, Daegu Gyeongbuk Institue of Science and Technology (DGIST), 42988 Daegu, Republic of Korea
5BioMedical Research Institute, Kyungpook National University Hospital, 41944 Daegu, Republic of Korea
6Department of Urology, School of Medicine, Kyungpook National University Hospital, 41944 Daegu, Republic of Korea
7BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 41571 Daegu, Republic of Korea
8Department of Urology, Yeungnam University College of Medicine, 42415 Daegu, Republic of Korea
DOI: 10.31083/j.jomh1807144 Vol.18,Issue 7,July 2022 pp.1-10
Submitted: 14 December 2021 Accepted: 10 January 2022
Published: 31 July 2022
*Corresponding Author(s): Tae Gyun Kwon E-mail: firstname.lastname@example.org
*Corresponding Author(s): Yun-Sok Ha E-mail: email@example.com
† These authors contributed equally.
Background: Prostate cancer is the second most common cause of cancer related death in males worldwide. Most patients show no response to androgen deprivation therapy in case of recurrence and proceed to advanced stage with metastasis. TRPM7 is reported to be upregulated in diverse types of tumors. Methods: We analyzed the expression of TRPM7 and related proteins by Western blotting analysis. We performed cell migration and invasion assay to analyze the relationship between tumor aggressiveness and TRPM7. In addition, we proceeded an animal study by using stable TRPM7 knockdown cell line in xenograft. Results: In our results, TRPM7 regulates prostate cancer cell biology including proliferation, migration and invasion through ERK1/2, PI3K/Akt and JNK signaling pathways. We produced stable TRPM7 knockdown prostate cancer cell line. To analyze the relationship between TRPM7 and tumorigenesis, we proceeded migration and invasion assay as well as xenograft model. TRPM7 down-regulated DU145 cells showed suppressed migratory and invasion ability, 0.65- and 0.05-fold, respectively. In addition, we confirmed that the anti-cancer effect of TRPM7 is mediated through inactivation of ERK1/2, Src and Akt signaling pathways by western blotting analysis. P-ERK1/2, p-Src, and p-Akt expressions were reduced to 0.66-, 0.68-, and 0.66-fold, respectively. Moreover, we treated ERK, Akt and Src inhibitors to clarify the involvement of related each protein in migration and invasion ability, and we could observe that inhibitor treated cells showed suppressed migration and invasion ability. In vivo, TRPM7 knockdown cells projected decreased cell proliferation rate. Conclusions: Taken these results together, out study suggested TRPM7 might be an essential gene for prostate cancer metastasis by regulating prostate cancer cell proliferation, migration and invasion ability.
Prostate cancer therapy; Transient receptor potential cation channel-subfamily M member 7; Migration ability; Cell proliferation; Src signaling
Eun Hye Lee,Jun Nyung Lee,Song Park,So Young Chun,Bo Hyun Yoon,Jae-Wook Chung,Seock Hwan Choi,Bum Soo Kim,Hyun Tae Kim,Tae Hwan Kim,Eun Sang Yoo,Sangkyu Lee,Jae Young Choi,Tae Gyun Kwon,Yun-Sok Ha. Inhibition of TRPM7 suppresses migration and invasion of prostate cancer cells via inactivation of ERK1/2, Src and Akt pathway signaling. Journal of Men's Health. 2022. 18(7);1-10.
 Gao H, Chen X, Du X, Guan B, Liu Y, Zhang H. EGF enhances the migration of cancer cells by up-regulation of TRPM7. Cell Calcium. 2011; 50: 559–568.
 Minke B. TRP channels and Ca2+ signaling. Cell Calcium. 2006; 40: 261–275.
 Park HS, Hong C, Kim BJ, So I. The Pathophysiologic Roles of TRPM7 Channel. the Korean Journal of Physiology & Pharmacol-ogy. 2014; 18: 15.
 Jin J, Desai BN, Navarro B, Donovan A, Andrews NC, Clapham DE. Deletion of Trpm7 disrupts embryonic development and thy-mopoiesis without altering Mg2+ homeostasis. Science. 2008; 322: 756–760.
 Kim BJ, Nah S, Jeon J, So I, Kim SJ. Transient Receptor Poten-tial Melastatin 7 Channels are Involved in Ginsenoside Rg3-Induced Apoptosis in Gastric Cancer Cells. Basic & Clinical Pharmacology & Toxicology. 2011; 109: 233–239.
 Sun Y, Selvaraj S, Varma A, Derry S, Sahmoun AE, Singh BB. Increase in Serum Ca2+/Mg2+ Ratio Promotes Proliferation of Prostate Cancer Cells by Activating TRPM7 Channels. Journal of Biological Chemistry. 2013; 288: 255–263.
 Lee EH, Chun SY, Kim B, Yoon BH, Lee JN, Kim BS, et al. Knock-down of TRPM7 prevents tumor growth, migration, and invasion through the Src, Akt, and JNK pathway in bladder cancer. BMC Urology. 2020; 20: 145.
 Ha Y, Kim Y, Yu NH, Chun SY, Choi SH, Lee JN, et al. Down-regulation of transient receptor potential melastatin member 7 pre-vents migration and invasion of renal cell carcinoma cells via in-activation of the Src and Akt pathway. Investigative and Clinical Urology. 2018; 59: 263.
 Gavin AT, Drummond FJ, Donnelly C, O’Leary E, Sharp L, Kinn-ear HR. Patient-reported ‘ever had’ and ‘current’ long-term physical symptoms after prostate cancer treatments. BJU International. 2015; 116: 397–406.
 Skinner HG, Schwartz GG. A Prospective Study of Total and Ion-ized Serum Calcium and Fatal Prostate Cancer. Cancer Epidemiol-ogy Biomarkers & Prevention. 2009; 18: 575–578.
 Skinner HG, Schwartz GG. Serum calcium and incident and fatal prostate cancer in the National Health and Nutrition Examination Survey. Cancer Epidemiology, Biomarkers & Prevention. 2008; 17: 2302–2305.
 Zhang H, Fang J, Yao D, Wu Y, Ip C, Dong Y. Activation of FOXO1 is critical for the anticancer effect of methylseleninic acid in prostate cancer cells. The Prostate. 2010; 70: 1265–1273.
 Ha Y, Kim S, Chung JI, Choi H, Kim JH, Yu HS, et al. Trends in End-of-Life Resource Utilization and Costs among Prostate Cancer Patients from 2006 to 2015: a Nationwide Population-Based Study. The World Journal of Men’s Health. 2021; 39: 158.
 Shin TJ, Jung W, Ha JY, Kim BH, Kim YH. The significance of the visible tumor on preoperative magnetic resonance imaging in localized prostate cancer. Prostate International. 2021; 9: 6–11.
 Agoulnik IU, Weigel NL. Androgen receptor action in hormone-dependent and recurrent prostate cancer. Journal of Cellular Bio-chemistry. 2006; 99: 362–372.
 Park JY, Choi P, Kim H, Kang KS, Ham J. Increase in apoptotic effect of Panax ginseng by microwave processing in human prostate cancer cells: in vitro and in vivo studies. Journal of Ginseng Research. 2016; 40: 62–67.
 Izumi K, Ikeda H, Maolake A, Machioka K, Nohara T, Narimoto K, et al. The relationship between prostate-specific antigen and TNM classification or Gleason score in prostate cancer patients with low prostate-specific antigen levels. The Prostate. 2015; 75: 1034–1042.
 Yallapu MM, Jaggi M, Chauhan SC. Beta-Cyclodextrin-curcumin self-assembly enhances curcumin delivery in prostate cancer cells. Colloids and Surfaces. B, Biointerfaces. 2010; 79: 113–125.
 Yang F, Cai J, Zhan H, Situ J, Li W, Mao Y, et al. Suppres-sion of TRPM7 Inhibited Hypoxia-Induced Migration and Inva-sion of Androgen-Independent Prostate Cancer Cells by Enhancing RACK1-Mediated Degradation of HIF-1α . Oxidative Medicine and Cellular Longevity. 2020; 2020: 1–15.
 Ha Y, Jeong P, Kim JS, Kwon W, Kim IY, Yun S, et al. Tumori-genic and prognostic significance of RASSF1a expression in low-grade (who grade 1 and grade 2) nonmuscle-invasive bladder cancer. Urology. 2012; 79: 1411.e1–1411.e6.
 Fleshner N. Defining high-risk prostate cancer: current status. the Canadian Journal of Urology. 2005; 12: 14–16.
 Tang J, Ahmad A, Sarkar FH. The role of microRNAs in breast cancer migration, invasion and metastasis. International Journal of Molecular Sciences. 2012; 13: 13414–13437.
 Xie D, Gore C, Liu J, Pong R, Mason R, Hao G, et al. Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107: 2485–2490.
 Wang J, Xiao L, Luo C, Zhou H, Hu J, Tang Y, et al. Overexpres-sion of TRPM7 is associated with poor prognosis in human ovarian carcinoma. Asian Pacific Journal of Cancer Prevention. 2014; 15: 3955–3958.
 Saini KS, Loi S, de Azambuja E, Metzger-Filho O, Saini ML, Igna-tiadis M, et al. Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer Treatment Re-views. 2013; 39: 935–946.
 Srinivasan R, Zabuawala T, Huang H, Zhang J, Gulati P, Fernandez S, et al. Erk1 and Erk2 regulate endothelial cell prolif-eration and migration during mouse embryonic angiogenesis. PLoS ONE. 2009; 4: e8283.
 Chen R, Ho Y, Guo H, Wang Y. Rapid activation of Stat3 and ERK1/2 by nicotine modulates cell proliferation in human bladder cancer cells. Toxicological Sciences. 2008; 104: 283–293.
 Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Al-imonti A, et al. Inhibition of mTORC1 leads to MAPK pathway ac-tivation through a PI3K-dependent feedback loop in human cancer. The Journal of Clinical Investigation. 2008; 118: 3065–3074.
 Irby RB, Yeatman TJ. Role of Src expression and activation in hu-man cancer. Oncogene. 2000; 19: 5636–5642.
 Yeatman TJ. A renaissance for SRC. Nature Reviews. Cancer. 2004; 4: 470–480.
 Bland JM, Altman DG. Transformations, means, and confidence in-tervals. British Medical Journal. 1996; 312: 1079.
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