The effects of aerobic exercise and gallic acid on prostate cancer-related autophagy pathway genes in rats
Subject Areas : Exercise Training and Diseases
1 - دانشجوی دکتری فیزیولوژی ورزش دانشگاه آزاد واحد تهران مرکز
Keywords: Aerobic exercise, gallic acid, Beclin-1, ATG5, and LC3,
Abstract :
Prostate cancer is one of the most common cancers. Regular physical activity and medicinal herbs can prevent their development by activating autophagy. However, the simultaneous effect of aerobic exercise and gallic acid on autophagic genes expression in prostate cancer tissues has not been studied. Accordingly, the present study determined the effect of aerobic exercise and gallic acid on the expression of Beclin-1, ATG5 and LC3 genes in the prostate tissue of male rats. In an experimental study, 60 male Wistar rats were randomly divided into 6 groups including 1-control-healthy group, 2-sham group, 3-control-prostate cancer group, 4-prostate cancer-aerobic exercise group, 5-prostate cancer-gallic acid group and 6-prostate cancer-aerobic exercise-gallic acid group. After prostate cancer was induced by inducing LNCaP and TSP-1-ENSCs cell lines, the subjects underwent aerobic exercise and gallic acid administration for eight weeks. At the end of the eighth week, the rats were sacrificed and their prostate tissue was removed. This was done to measure the expression of Beclin-1, ATG5 and LC3 genes by Real-Time PCR. Expression of BECLIN1 (P=0.019), ATG5 (P=0.001) and LC3 (P=0.001) genes was significantly lower in the control-prostate cancer induction group than in the control-healthy group. The expression of BECLIN1, ATG5 and LC3 genes was significantly higher in the aerobic exercise-prostate cancer group, the gallic acid-prostate cancer group and the aerobic exercise-gallic acid-prostate cancer group than in the control-prostate cancer group. According to the study results, it is concluded that aerobic exercise and gallic acid promote autophagy in prostate cancer tissue. It seems that the combination of these two interventions can be used as an effective strategy for managing and preventing disease progression.
References:
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1(3), September 2024, 160-169
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33-Qiu D.M., Wang G.L., Chen L., Xu Y.Y., He S., Cao X.L., Qin J., Zhou J.M., Zhang Y.X., E Q. The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic significance. BMC Cancer. 2014;14:327.
34-Huang X., Bai H.M., Chen L., Li B., Lu Y.C. Reduced expression of LC3B-II and Beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors. J. Clin. Neurosci. 2010;17:1515–1519.
35- Jin S, White E. Role of autophagy in cancer: management of metabolic stress. Autophagy. 2007 Jan-Feb;3(1):28-31.
36- Li Z, Chen B, Wu Y, Jin F, Xia Y, Liu X. Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors. BMC Cancer. 2010 Mar 16;10:98.
37- Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol. 2006; 8: 1124–1132.
38- Chai P, Ni H, Zhang H Fan X. The Evolving Functions of Autophagy in Ocular Health: A Double-edged Sword. Int J Biol Sci. 2016; 12: 1332–1340.
39- Yousefi S Simon HU. Apoptosis regulation by autophagy gene 5. Crit Rev Oncol Hematol. 2007; 63: 241–244.
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41- Pierdominici M, Vomero M, Barbati C, Colasanti T, Maselli A, Vacirca D, et al. Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. FASEB J. (2012) 26:1400–12.
42- Mochida K., Oikawa Y., Kimura Y., Kirisako H., Hirano H., Ohsumi Y., Nakatogawa H. Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. Nature. 2015;522:359–362.
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44- Saitoh T., Fujita N., Jang M.H., Uematsu S., Yang B.G., Satoh T., Omori H., Noda T., Yamamoto N., Komatsu M., et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456:264–268.
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46- Liu H., He Z., von Rutte T., Yousefi S., Hunger R.E., Simon H.U. Down-regulation of autophagy-related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma. Sci. Transl. Med. 2013;5:202ra123.
47- Vescovo T, Pagni B, Piacentini M, Fimia GM, Antonioli M. Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development. Front Cell Dev Biol. 2020 Feb 28;8:47.
48- Aryal P, Kim K, Park PH, Ham S, Cho J, Song K. Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells. FEBS J. 2014 Oct;281(20):4644-58.
49- Miracco C, Cevenini G, Franchi A, Luzi P, Cosci E, Mourmouras V, et al. Beclin 1 and LC3 autophagic gene expression in cutaneous melanocytic lesions. Hum Pathol. 2010;41(4):503–12.
50- Bryan AD, Magnan RE, Hooper AE, Harlaar N, Hutchison KE. Physical activity and differential methylation of breast cancer genes assayed from saliva: a preliminary investigation. Ann Behav Med. 2013 Feb;45(1):89-98.
51- Jurkowska RZ, Jorkowski TP, Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011;24:206–222.
52- Zeng H, Irwin ML, Lu L, Risch H, Mayne S, Mu L. Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1. Breast Cancer Res Treat. 2012;133:127–35.
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54- Abla H, Sollazzo M, Gasparre G, Iommarini L, Porcelli AM. The multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit? Semin Cell Dev Biol. 2020 Feb;98:26-33.
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57- Moghtaderi, H. , Sepehri, H. , Delphi, L. , & Attari, F. (2018). Gallic acid and curcumin induce cytotoxicity and apoptosis in human breast cancer cell MDA‐MB‐231. BioImpacts: BI, 8, 185–194.
58- Subramanian, A. P. , John, A. A. , Vellayappan, M. V. , Balaji, A. , Jaganathan, S. K. , Supriyanto, E. , & Yusof, M. (2015). Gallic acid: Prospects and molecular mechanisms of its anticancer activity. RSC Advances, 5, 35608–35621.
59- Chen, H.‐M. , Wu, Y.‐C. , Chia, Y.‐C. , Chang, F.‐R. , Hsu, H.‐K. , Hsieh, Y.‐C. , Chen, C.‐C. , & Yuan, S.‐S. (2009). Gallic acid, a major component of Toona sinensis leaf extracts, contains a ROS‐mediated anti‐cancer activity in human prostate cancer cells. Cancer Letters, 286, 161–171.
60- Liu, C. , Ho, P. C.‐L. , Wong, F. C. , Sethi, G. , Wang, L. Z. , & Goh, B. C. (2015). Garcinol: Current status of its anti‐oxidative, anti‐inflammatory and anti‐cancer effects. Cancer Letters, 362, 8–14.
61- Meng, M. (2011). Gallic acid suppresses the migration and invasion of PC‐3 human prostate cancer cells via inhibition of matrix metalloproteinase‐2 and ‐9 signaling pathways. Oncology Reports, 26, 177–184.
1- Liu C, Xu P, Chen D, Fan X, Xu Y, Li M, Yang X, Wang C. Roles of autophagy-related genes Beclin-1 and LC3 in the development and progression of prostate cancer and benign prostatic hyperplasia. Biomed Rep. 2013 Nov;1(6):855-860.
2-Sim HG, Cheng CW. Changing demography of prostate cancer in Asia. Eur J Cancer. 2005;41:834–845.
3- Ashrafizadeh, M., Paskeh, M.D.A., Mirzaei, S. et al. Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response. J Exp Clin Cancer Res 41, 105 (2022).
4-Mizushima N. Autophagy: Process and function. Genes Dev. 2007;21:2861–2873
5-Mizushima N. The pleiotropic role of autophagy: From protein metabolism to bactericide. Cell Death Differ. 2005;12(Suppl. 2):1535–1541.
6-Yun CW, Lee SH. The Roles of Autophagy in Cancer. Int J Mol Sci. 2018 Nov 5;19(11):3466.
7- Kim, JS., Galvão, D.A., Newton, R.U. et al. Exercise-induced myokines and their effect on prostate cancer. Nat Rev Urol 18, 519–542 (2021).
8- Madison Webber , Muqing Li , Changmeng Cai , Kai Zou .Effects of exercise training on prostate cancer: Current evidence and potential molecular mechanisms. Advanced Exercise and Health Science
1(3), September 2024, 160-169
9- Rocha-Rodrigues S, Matos A, Afonso J, Mendes-Ferreira M, Abade E, Teixeira E, Silva B, Murawska-Ciałowicz E, Oliveira MJ, Ribeiro R. Skeletal Muscle-Adipose Tissue-Tumor Axis: Molecular Mechanisms Linking Exercise Training in Prostate Cancer. Int J Mol Sci. 2021 Apr 25;22(9):4469.
10- Friedenreich CM, Wang Q, Neilson HK, Kopciuk KA, McGregor SE, Courneya KS. Physical Activity and Survival After Prostate Cancer. Eur Urol. 2016 Oct;70(4):576-585.
11- Gunadi JW, Welliangan AS, Soetadji RS, Jasaputra DK, Lesmana R. The Role of Autophagy Modulated by Exercise in Cancer Cachexia. Life (Basel). 2021 Aug 2;11(8):781.
12- Levy J.M.M., Thorburn A. Autophagy in cancer: Moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ. 2020;27:843–857.
13- Chen H.-Y., White E. Role of Autophagy in Cancer Prevention. Cancer Prev. Res. 2011;4:973–983.
14- Jiang, Y., Pei, J., Zheng, Y. et al. Gallic Acid: A Potential Anti-Cancer Agent. Chin. J. Integr. Med. 28, 661–671 (2022).
15- Yang K, Zhang L, Liao P, Xiao Z, Zhang F, Sindaye D, Xin Z, Tan C, Deng J, Yin Y, Deng B. Impact of Gallic Acid on Gut Health: Focus on the Gut Microbiome, Immune Response, and Mechanisms of Action. Front Immunol. 2020 Sep 16;11:580208.
16- Fernandes FH, Salgado HR. Gallic Acid: Review of the Methods of Determination and Quantification. Crit Rev Anal Chem. 2016 May 3;46(3):257-65.
17- Moghtaderi, H. , Sepehri, H. , Delphi, L. , & Attari, F. (2018). Gallic acid and curcumin induce cytotoxicity and apoptosis in human breast cancer cell MDA‐MB‐231. BioImpacts: BI, 8, 185–194.
18- Subramanian, A. P. , John, A. A. , Vellayappan, M. V. , Balaji, A. , Jaganathan, S. K. , Supriyanto, E. , & Yusof, M. (2015). Gallic acid: Prospects and molecular mechanisms of its anticancer activity. RSC Advances, 5, 35608–35621.
19- Chen, H.‐M. , Wu, Y.‐C. , Chia, Y.‐C. , Chang, F.‐R. , Hsu, H.‐K. , Hsieh, Y.‐C. , Chen, C.‐C. , & Yuan, S.‐S. (2009). Gallic acid, a major component of Toona sinensis leaf extracts, contains a ROS‐mediated anti‐cancer activity in human prostate cancer cells. Cancer Letters, 286, 161–171.
20- Liu, C. , Ho, P. C.‐L. , Wong, F. C. , Sethi, G. , Wang, L. Z. , & Goh, B. C. (2015). Garcinol: Current status of its anti‐oxidative, anti‐inflammatory and anti‐cancer effects. Cancer Letters, 362, 8–14.
21- Meng, M. (2011). Gallic acid suppresses the migration and invasion of PC‐3 human prostate cancer cells via inhibition of matrix metalloproteinase‐2 and ‐9 signaling pathways. Oncology Reports, 26, 177–184.
22- Attar Shakri, Hossein, Fattahi, Esmail, Nowrozi, Mohammad Reza, Momeni, Seyed Ali, Piriaei, Abbas. Investigating the combined effect of endostatin with endometrial stem cells expressing the anti-angiogenic gene TSP-1 on angiogenesis-inducing factors in the treatment of rat prostate cancer. Animal Biology Quarterly, 2019; 13(2): 101-114.
23- Danielle J. McCullough, Linda M.-D. Nguyen, Dietmar W. Siemann, and Bradley J. Behnke
Journal of Applied Physiology 2013 115:12, 1846-1854 . Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model
24-Ojo, D. E., A. B., Ogunlakin, A. D., & Ajiboye, B. O. (2023). Gallic acid abates cadmium chloride toxicity via alteration of neurotransmitters and modulation of inflammatory markers in Wistar rats. Scientific Reports, 13(1), 1577
25- Lim K.H., Staudt L.M. Toll-like receptor signaling. Cold Spring Harbor Perspect. Biol. 2013;5:a011247.
26-Salminen A., Kaarniranta K., Kauppinen A. Beclin 1 interactome controls the crosstalk between apoptosis, autophagy and inflammasome activation: Impact on the aging process. Ageing Res. Rev. 2013;12:520–534.
27-Rosenfeldt M.T., Ryan K.M. The multiple roles of autophagy in cancer. Carcinogenesis. 2011;32:955–963. doi: 10.1093/carcin/bgr031. [DOI] [PMC free article] [PubMed] [Google Scholar]
28-Gewirtz D.A. The four faces of autophagy: Implications for cancer therapy. Cancer Res. 2014;74:647–651.
29- Qu X., Yu J., Bhagat G., Furuya N., Hibshoosh H., Troxel A., Rosen J., Eskelinen E.L., Mizushima N., Ohsumi Y., et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Investig. 2003;112:1809–1820.
30-Shen Y., Li D.D., Wang L.L., Deng R., Zhu X.F. Decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer. Autophagy. 2008;4:1067–1068.
31-Yue Z., Jin S., Yang C., Levine A.J., Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. USA. 2003;100:15077–15082.
32-Cai M., Hu Z., Liu J., Gao J., Liu C., Liu D., Tan M., Zhang D., Lin B. Beclin 1 expression in ovarian tissues and its effects on ovarian cancer prognosis. Int. J. Mol. Sci. 2014;15:5292–5303.
33-Qiu D.M., Wang G.L., Chen L., Xu Y.Y., He S., Cao X.L., Qin J., Zhou J.M., Zhang Y.X., E Q. The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic significance. BMC Cancer. 2014;14:327.
34-Huang X., Bai H.M., Chen L., Li B., Lu Y.C. Reduced expression of LC3B-II and Beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors. J. Clin. Neurosci. 2010;17:1515–1519.
35- Jin S, White E. Role of autophagy in cancer: management of metabolic stress. Autophagy. 2007 Jan-Feb;3(1):28-31.
36- Li Z, Chen B, Wu Y, Jin F, Xia Y, Liu X. Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors. BMC Cancer. 2010 Mar 16;10:98.
37- Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol. 2006; 8: 1124–1132.
38- Chai P, Ni H, Zhang H Fan X. The Evolving Functions of Autophagy in Ocular Health: A Double-edged Sword. Int J Biol Sci. 2016; 12: 1332–1340.
39- Yousefi S Simon HU. Apoptosis regulation by autophagy gene 5. Crit Rev Oncol Hematol. 2007; 63: 241–244.
40- Yao Z, Delorme-Axford E, Backues SK, Klionsky DJ. Atg41/Icy2 regulates autophagosome formation. Autophagy (2015) 11:2288–99.
41- Pierdominici M, Vomero M, Barbati C, Colasanti T, Maselli A, Vacirca D, et al. Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. FASEB J. (2012) 26:1400–12.
42- Mochida K., Oikawa Y., Kimura Y., Kirisako H., Hirano H., Ohsumi Y., Nakatogawa H. Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. Nature. 2015;522:359–362.
43- Takamura A., Komatsu M., Hara T., Sakamoto A., Kishi C., Waguri S., Eishi Y., Hino O., Tanaka K., Mizushima N. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011;25:795–800
44- Saitoh T., Fujita N., Jang M.H., Uematsu S., Yang B.G., Satoh T., Omori H., Noda T., Yamamoto N., Komatsu M., et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456:264–268.
45- Sou Y.S., Waguri S., Iwata J., Ueno T., Fujimura T., Hara T., Sawada N., Yamada A., Mizushima N., Uchiyama Y., et al. The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol. Biol. Cell. 2008;19:4762–4775.
46- Liu H., He Z., von Rutte T., Yousefi S., Hunger R.E., Simon H.U. Down-regulation of autophagy-related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma. Sci. Transl. Med. 2013;5:202ra123.
47- Vescovo T, Pagni B, Piacentini M, Fimia GM, Antonioli M. Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development. Front Cell Dev Biol. 2020 Feb 28;8:47.
48- Aryal P, Kim K, Park PH, Ham S, Cho J, Song K. Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells. FEBS J. 2014 Oct;281(20):4644-58.
49- Miracco C, Cevenini G, Franchi A, Luzi P, Cosci E, Mourmouras V, et al. Beclin 1 and LC3 autophagic gene expression in cutaneous melanocytic lesions. Hum Pathol. 2010;41(4):503–12.
50- Bryan AD, Magnan RE, Hooper AE, Harlaar N, Hutchison KE. Physical activity and differential methylation of breast cancer genes assayed from saliva: a preliminary investigation. Ann Behav Med. 2013 Feb;45(1):89-98.
51- Jurkowska RZ, Jorkowski TP, Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011;24:206–222.
52- Zeng H, Irwin ML, Lu L, Risch H, Mayne S, Mu L. Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1. Breast Cancer Res Treat. 2012;133:127–35.
53- Światowy, W.J.; Drzewiecka, H.; Kliber, M.; Sąsiadek, M.; Karpiński, P.; Pławski, A.; Jagodziński, P.P. Physical Activity and DNA Methylation in Humans. IJMS 2021, 22, 12989.
54- Abla H, Sollazzo M, Gasparre G, Iommarini L, Porcelli AM. The multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit? Semin Cell Dev Biol. 2020 Feb;98:26-33.
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