PGC1-α mRNA expression cross talk with tumor volume growth and total antioxidant capacity in breast cancer model mice: following discontinuous aerobic exercise and vitamin D intake

Document Type : Original Article


1 Department of Physical Education and Sport Sciences, University of Kurdistan, Sanandaj, Iran.

2 Collage of Physical Education and Sport Sciences, University of Kharazmi, Tehran, Iran.

3 Department of Biological Sciences, University of Kurdistan, Sanandaj, Iran.


The modifications of PGC-1𝛼 induce the change of the carcinogenesis and tumor growth and lead to increased antioxidant enzymes. The present study aimed to determine the cross talk between PGC1-α mRNA expression, tumor volume growth, and total antioxidant capacity in breast cancer model mice, followed by discontinuous aerobic exercise and vitamin D. In the present study, 40 female NMRI mice were randomly assigned into five equal groups (n=8): healthy control group (H.C), cancer control group (Ca.C), cancer with the vitamin D group (U.Ca.VD), cancer exercise training group (Ca. Ex), and cancer exercise training with the vitamin D group (Ca.Ex.VD). As the results indicate, the bodyweight of cancer groups (p=0.041, F=3.61) and the tumor growth rate significantly reduced compared to the H.C group. The results indicated that the PGC-1α mRNA expression and TAC (p=0.013, F=5.16) change significantly different between the study groups. Besides, based on the results, a significant positive correlation was observed between PGC1-α and tumor volume growth among the groups, whereas a negative relationship exists between PGC1-α and TAC and among TAC and tumor volume growth only in the Ca. Ex.VD group. The correlation between the variables confirms using vitamin D treatment with the implementation of discontinuous aerobic exercise, as a synergistic effect, improves the total antioxidant capacity and is effective in controlling tumor growth. We recommend that further studies be done on exercise training along with supplementation intake synergistic.

What is already known on this subject?

PGC-1α promotes breast cancer metastasis and confers bioenergetics flexibility against metabolic drugs but with the intervention of exercise training and vitamin D, a different issue is raised for which a definite answer has not been given yet.


What this study adds?

We know that taking vitamin D supplementation along with implementation of discontinuous aerobic exercise as a synergistic effect improves the total antioxidant capacity and is effective in controlling tumor growth.


Main Subjects

Alvarado, A., Faustino-Rocha, A. I., Ferreira, R., Mendes, R., Duarte, J. A., Pires, M. J., et al. (2016). Prognostic factors in an exercised model of chemically-induced mammary cancer. Anticancer Res, 36(5), 2181-2188. PMID: 27127121
Andrzejewski, S., Klimcakova, E., Johnson, R. M., Tabaries, S., Annis, M. G., Mcguirk, S., et al. (2017). PGC-1α promotes breast cancer metastasis and confers bioenergetic flexibility against metabolic drugs. Cell Metab, 26(5), 778-787.e775. doi:
Atoum, M., & Alzoughool, F. (2017). Vitamin D and breast cancer: Latest evidence and future steps. Breast Cancer (Auckl), 11, 1178223417749816. doi:
Bhalla, K., Hwang, B. J., Dewi, R. E., Ou, L., Twaddel, W., Fang, H. B., et al. (2011). PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis. Cancer Res, 71(21), 6888-6898. doi:
Chen, Y., Zhang, J., Lin, Y., Lei, Q., Guan, K.-L., Zhao, S., et al. (2011). Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Reports, 12(6), 534-541. doi:
Clarkson, P. M., & Thompson, H. S. (2000). Antioxidants: What role do they play in physical activity and health? Am J Clin Nutr, 72(2 Suppl), 637s-646s. doi:
Demarzo, M. M., & Garcia, S. B. (2004). Exhaustive physical exercise increases the number of colonic preneoplastic lesions in untrained rats treated with a chemical carcinogen. Cancer Lett, 216(1), 31-34. doi:
Demarzo, M. M., Martins, L. V., Fernandes, C. R., Herrero, F. A., Perez, S. E., Turatti, A., et al. (2008). Exercise reduces inflammation and cell proliferation in rat colon carcinogenesis. Med Sci Sports Exerc, 40(4), 618-621. doi:
Fairey, A. S., Courneya, K. S., Field, C. J., Bell, G. J., Jones, L. W., & Mackey, J. R. (2005). Randomized controlled trial of exercise and blood immune function in postmenopausal breast cancer survivors. J Appl Physiol (1985), 98(4), 1534-1540. doi:
Fajas, L., Auboeuf, D., Raspe, E., Schoonjans, K., Lefebvre, A. M., Saladin, R., et al. (1997). The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem, 272(30), 18779-18789. doi:
Faustino-Rocha, A. I., Gama, A., Oliveira, P. A., Alvarado, A., Neuparth, M. J., Ferreira, R., et al. (2017). Effects of lifelong exercise training on mammary tumorigenesis induced by MNU in female Sprague-Dawley rats. Clin Exp Med, 17(2), 151-160. doi:
Faustino-Rocha, A. I., Silva, A., Gabriel, J., Gil Da Costa, R. M., Moutinho, M., Oliveira, P. A., et al. (2016). Long-term exercise training as a modulator of mammary cancer vascularization. Biomed Pharmacother, 81, 273-280. doi:
Fisher, K. W., Das, B., Kortum, R. L., Chaika, O. V., & Lewis, R. E. (2011). Kinase suppressor of ras 1 (KSR1) regulates PGC1α and estrogen-related receptor α to promote oncogenic Ras-dependent anchorage-independent growth. Mol Cell Biol, 31(12), 2453-2461. doi:
Guo, L. (2021). Mitochondria and the permeability transition pore in cancer metabolic reprogramming. Biochem Pharmacol, 188, 114537. doi: 2021.114537
Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., et al. (2013). Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell, 23(3), 302-315. doi:
Hutnick, N. A., Williams, N. I., Kraemer, W. J., Orsega-Smith, E., Dixon, R. H., Bleznak, A. D., et al. (2005). Exercise and lymphocyte activation following chemotherapy for breast cancer. Med Sci Sports Exerc, 37(11), 1827-1835. doi:
Jafari, A., Sheikholeslami-Vatani, D., Khosrobakhsh, F., & Khaledi, N. (2021). Synergistic effects of exercise training and vitamin D supplementation on mitochondrial function of cardiac tissue, antioxidant capacity, and tumor growth in breast cancer in bearing-4T1 mice. Frontiers in Physiology, 12(465). doi:
Jeon, S. M., & Shin, E. A. (2018). Exploring vitamin D metabolism and function in cancer. Exp Mol Med, 50(4), 1-14. doi:
Jones, A. W., Yao, Z., Vicencio, J. M., Karkucinska-Wieckowska, A., & Szabadkai, G. (2012). PGC-1 family coactivators and cell fate: Roles in cancer, neurodegeneration, cardiovascular disease and retrograde mitochondria-nucleus signalling. Mitochondrion, 12(1), 86-99. doi:
Jones, L. W., Eves, N. D., Peddle, C. J., Courneya, K. S., Haykowsky, M., Kumar, V., et al. (2009). Effects of presurgical exercise training on systemic inflammatory markers among patients with malignant lung lesions. Appl Physiol Nutr Metab, 34(2), 197-202. doi:
Jones, L. W., Viglianti, B. L., Tashjian, J. A., Kothadia, S. M., Keir, S. T., Freedland, S. J., et al. (2010). Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. J Appl Physiol (1985), 108(2), 343-348. doi:
Lebleu, V. S., O'connell, J. T., Gonzalez Herrera, K. N., Wikman, H., Pantel, K., Haigis, M. C., et al. (2014). PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol, 16(10), 992-1003, 1001-1015. doi:
Lee, H. J., Su, Y., Yin, P. H., Lee, H. C., & Chi, C. W. (2009). PPAR(gamma)/PGC-1(alpha) pathway in E-cadherin expression and motility of HepG2 cells. Anticancer Res, 29(12), 5057-5063. PMID: 20044617
Lee, C. H., Wu, S. B., Hong, C. H., Liao, W. T., Wu, C. Y., Chen, G. S., et al. (2011). Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers. Am J Pathol, 178(5), 2066-2076. doi: 2011.01.056
Malicka, I., Siewierska, K., Pula, B., Kobierzycki, C., Haus, D., Paslawska, U., et al. (2015). The effect of physical training on the N-methyl-N-nitrosourea-induced mammary carcinogenesis of Sprague-Dawley rats. Exp Biol Med (Maywood), 240(11), 1408-1415. doi:
Mcguirk, S., Gravel, S.-P., Deblois, G., Papadopoli, D. J., Faubert, B., Wegner, A., et al. (2013). PGC-1α supports glutamine metabolism in breast cancer. Cancer & Metabolism, 1(1), 1-11. doi:
Moyses-Oliveira, M., Cabral, V., Gigek, C. O., Correa, D. C. C., Di-Battista, A., Stumpp, T., et al. (2019). Search for appropriate reference genes for quantitative reverse transcription PCR studies in somite, prosencephalon and heart of early mouse embryo. Gene, 710, 148-155. doi:
O'malley, M., King, A. N., Conte, M., Ellingrod, V. L., & Ramnath, N. (2014). Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer. J Thorac Oncol, 9(7), 917-926. doi: 0000000000000191
Patti, M. E., Butte, A. J., Crunkhorn, S., Cusi, K., Berria, R., Kashyap, S., et al. (2003). Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential Role of PGC1 and NRF1. Proc Natl Acad Sci U S A, 100(14), 8466-8471. doi:
Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M., & Spiegelman, B. M. (1998). A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell, 92(6), 829-839. doi:
Ramez, M., Ramezani, F., Nasirinezhad, F., & Rajabi, H. (2020). High-intensity interval training increases myocardial levels of Klotho and protects the heart against ischaemia-reperfusion injury. Exp Physiol, 105(4), 652-665. doi:
Ramnath, N., Nadal, E., Jeon, C. K., Sandoval, J., Colacino, J., Rozek, L. S., et al. (2014). Epigenetic regulation of vitamin D metabolism in human lung adenocarcinoma. J Thorac Oncol, 9(4), 473-482. doi:
Ricca, C., Aillon, A., Bergandi, L., Alotto, D., Castagnoli, C., & Silvagno, F. (2018). Vitamin D receptor is necessary for mitochondrial function and cell health. International Journal of Molecular Sciences, 19(6). doi:
Schlotter, C. M., Vogt, U., Allgayer, H., & Brandt, B. (2008). Molecular targeted therapies for breast cancer treatment. Breast Cancer Res, 10(4), 211. doi:
Shin, S. W., Yun, S. H., Park, E. S., Jeong, J. S., Kwak, J. Y., & Park, J. I. (2015). Overexpression of PGC‑1α enhances cell proliferation and tumorigenesis of HEK293 cells through the upregulation of Sp1 and Acyl-CoA binding protein. Int J Oncol, 46(3), 1328-1342. doi:
Shiota, M., Yokomizo, A., Tada, Y., Inokuchi, J., Tatsugami, K., Kuroiwa, K., et al. (2010). Peroxisome proliferator-activated receptor gamma coactivator-1alpha interacts with the androgen receptor (AR) and promotes prostate cancer cell growth by activating the AR. Mol Endocrinol, 24(1), 114-127. doi:
Singh, M. P., Singh, G., & Singh, S. M. (2005). Role of host's antitumor immunity in exercise-dependent regression of murine T-cell lymphoma. Comp Immunol Microbiol Infect Dis, 28(3), 231-248. doi:
Song, C., Fu, B., Zhang, J., Zhao, J., Yuan, M., Peng, W., et al. (2017). Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway. Sci Rep, 7(1), 672. doi:
Steiner, J. L., Davis, J. M., Mcclellan, J. L., Enos, R. T., & Murphy, E. A. (2013). Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer. Int J Oncol, 42(4), 1466-1472. doi:
Sturgeon, K. M., Schweitzer, A., Leonard, J. J., Tobias, D. K., Liu, Y., Cespedes Feliciano, E., et al. (2017). Physical activity induced protection against breast cancer risk associated with delayed parity. Physiol Behav, 169, 52-58. doi:
Taguchi, A., Delgado, O., Celiktaş, M., Katayama, H., Wang, H., Gazdar, A. F., et al. (2014). Proteomic signatures associated with p53 mutational status in lung adenocarcinoma. Proteomics, 14(23-24), doi: 2750-2759. 201400378
Tennakoon, J. B., Shi, Y., Han, J. J., Tsouko, E., White, M. A., Burns, A. R., et al. (2014). Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch. Oncogene, 33(45), 5251-5261. doi:
Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I., & Spiegelman, B. M. (1994). mPPAR gamma 2: Tissue-specific regulator of an adipocyte enhancer. Genes Dev, 8(10), 1224-1234. doi:
Vazquez, F., Lim, J. H., Chim, H., Bhalla, K., Girnun, G., Pierce, K., et al. (2013). PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell, 23(3), 287-301. doi:
Wang, M., Yu, B., Westerlind, K., Strange, R., Khan, G., Patil, D., et al. (2009). Prepubertal physical activity up-regulates estrogen receptor beta, BRCA1 and p53 mRNA expression in the rat mammary gland. Breast Cancer Res Treat, 115(1), 213-220. doi:
Watanabe, R., & Inoue, D. (2015). Current topics on vitamin D. Anti-cancer effects of vitamin D. Clin Calcium, 25(3), 373-380. Watkins, G., Douglas-Jones, A., Mansel, R. E., & Jiang, W. G. (2004). The localisation and reduction of nuclear staining of PPARgamma and PGC-1 in human breast cancer. Oncol Rep, 12(2), 483-488.
Weikum, E. R., Liu, X., & Ortlund, E. A. (2018). The nuclear receptor superfamily: A structural perspective. Protein Sci, 27(11), 1876-1892. doi:
Westerlind, K. C., Mccarty, H. L., Schultheiss, P. C., Story, R., Reed, A. H., Baier, M. L., et al. (2003). Moderate exercise training slows mammary tumour growth in adolescent rats. Eur J Cancer Prev, 12(4), 281-287. doi:
Wimalawansa, S. J. (2019). Vitamin D deficiency: Effects on oxidative stress, epigenetics, gene regulation, and aging. Biology (Basel), 8(2). doi:
Wolin, K. Y., Schwartz, A. L., Matthews, C. E., Courneya, K. S., & Schmitz, K. H. (2012). Implementing the exercise guidelines for cancer survivors. J Support Oncol, 10(5), 171-177. doi:
Wu, W., & Zhao, S. (2013). Metabolic changes in cancer: beyond the Warburg effect. Acta Biochim Biophys Sin (Shanghai), 45(1), 18-26. doi:
Yu, H., & Xin, Y. (2013). Down-regulated expressions of PPARγ and its coactivator PGC-1 are related to gastric carcinogenesis and Lauren's classification in gastric carcinoma. Chin J Cancer Res, 25(6), 704-714. doi:
Zhang, Y., Ba, Y., Liu, C., Sun, G., Ding, L., Gao, S., et al. (2007). PGC-1alpha induces apoptosis in human epithelial ovarian cancer cells through a PPARgamma-dependent pathway. Cell Res, 17(4), 363-373.