Investigation the Role of miR-506 in Metformin-Induced Cell Death Mechanism in MCF-7 and MDA-MB-231 Breast Cancer Cells

Yıl 2024, Cilt: 20 Sayı: 3, 1 - 9, 30.09.2024

Özge Rencuzoğulları , Suraya Qayoumi

https://doi.org/10.18466/cbayarfbe.1453535

Öz

Micro RNAs (miRNA) play a role in basic cellular processes such as cell growth, development, cell cycle and apoptosis by affecting gene expression. Abnormal regulation or changes in expression of miRNAs can be observed in many diseases, especially cancer. Therefore, miRNAs are also being investigated as potential therapeutic targets. It has been suggested that miR-506 may be expressed at low levels in various types of cancer and this may contribute to cancer development. In this study, the effect of miR-506 on the sensitivity of breast cancer cells to metformin was evaluated in terms of its effect on cell survival and apoptotic mechanism. Metformin caused a dose-dependent decrease in cell viability and induced loss of mitochondrial membrane potential in MCF-7 cells while MDA-MB-231 cells were more resistant. The colony formation and migration potential of both cell lines with increased miR-506 expression were significantly suppressed after metformin treatment. Additionally, apoptotic cell death triggered by metformin was induced in both cell lines when miR-506 expression was increased. In conclusion, miR-506 acts as a tumor suppressor in MCF-7 and MDA-MB-231 cells and increases their sensitivity to metformin, indicating the potential of miR-506 to be an important therapeutic target in future studies.

Anahtar Kelimeler

Apoptotic cell death, Breast cancer, Metformin, miR-506

Etik Beyan

There are no ethical issues after the publication of this manuscript.

Destekleyen Kurum

İstanbul Kültür Üniversitesi

Teşekkür

The authors wish to thank Scientific Research Projects Unit of Istanbul Kultur University for their constant interest in this project.

Kaynakça

• [1]. Otmani K., Lewalle P. 2021. Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications. Front. Oncol.; 11: 708-765.
• [2]. Michlewski G., Cáceres J. F. 2019. Post-transcriptional control of miRNA biogenesis. RNA; 25(1): 1–16.
• [3]. Muñoz J. P., Pérez-Moreno P., Pérez Y., Calaf G. M. 2023. The Role of MicroRNAs in Breast Cancer and the Challenges of Their Clinical Application., Diagnostics (Basel, Switzerland); 13(19): 3072.
• [4]. Annese T., Tamma R., De Giorgis M., Ribatti D. 2020. microRNAs Biogenesis, Functions and Role in Tumor Angiogenesis., Front. Oncol.; 10(1): 581007-58127.
• [5]. Wen S.Y., Lin Y., Yu YQ., Cao S.J., Zhang R., Yang X.M., Li J., Zhang Y.L., Wang Y.H., Ma M.Z., Sun W.W., Lou X.L., Wang J.H., Teng Y.C., Zhang Z.G. 2015. miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene; 34(6): 717–725.
• [6]. Saad El Din G., Youness R. A., Assal R. A., Gad M. Z. 2018. Mir-506-3p synergistically represses breast cancer progression through altering cell cycle regulators. Ann. Oncol; 29: 28-34.
• [7]. Lu C.C., Chiang J.H., Tsai F.J., Hsu Y.M., Juan Y.N., Yang J.S., Chiu H.Y. 2019. Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling, Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. Int. J. Oncol; 54(4): 1271–1281.
• [8]. Balkan B., Demir G., Balkan F., Çetingök H., Atiç E. 2020. Metformin İlişkili Laktik Asidoz; Bir Olgu Nedeni ile Literatürün Gözden Geçirilmesi, Tıp Fakültesi Klinikleri Dergisi; 3(1): 49-53.
• [9]. Samuel S. M., Varghese E., Koklesová L., Líšková A., Kubatka P., Büsselberg D. 2020. Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells., Cancers (Basel); 12 (9): 2482-2490.
• [10]. Amaral I., Silva C., Correia-Branco A., and Martel F. 2017. Metformin interferes with glucose cellular uptake by both estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines: PS156. Porto Biomed. J.; 2(5): 218-226.
• [11]. Li B., Zhou P., Xu K., Chen T., Jiao J., Wei H., Yang X., Xu W., Wan W., Xiao J. 2020. Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma. Int. J. Biol. Sci.; 16 (1): 74–84.
• [12]. Szymczak-Pajor I., Drzewoski J., Świderska E., Strycharz J., Gabryanczyk A., Kasznicki J., Bogdańska M., Śliwińska A. 2023. Metformin Induces Apoptosis in Human Pancreatic Cancer (PC) Cells Accompanied by Changes in the Levels of Histone Acetyltransferases (Particularly, p300/CBP-Associated Factor (PCAF) Protein Levels). Pharmaceuticals; 16(1): 115-123.
• [13]. Zhu M., Wang J., and Zhou R. 2022. Combination of metformin and oxaliplatin inhibits gastric cancer cell proliferation and induces apoptosis. Acta Biochim. Pol.; 69(2): 321–326.
• [14]. Elmore S. 2007. Apoptosis: a review of programmed cell death. Toxicol. Pathol.; 35 (4) (2007) 495–516.
• [15]. Rencüzoğullari Ö., Arisan E. D. 2022. Palbociclib suppresses the cancer stem cell properties and cell proliferation through increased levels of miR-506 or miR-150 in Panc-1 and MiaPaCa-2 cells. Turkish J. Biol., 46(5): 342–360.
• [16]. Gao Z.Y., Liu Z., Bi M.H., Zhang J.J., Han Z.Q., Han X., Wang H.Y., Sun G.P., Liu H., Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro. Exp. Ther. Med.; 11(5): 1700–1706.
• [17]. Chen Y.H., Yang S.F., Yang C.K., Tsai H.D., Chen T.H., Chou M.C., Hsiao Y.H. 2021. Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells. Mol. Med. Rep.; 23(1): 88-97.
• [18]. Streicher K.L., Zhu W., Lehmann K.P., Georgantas R.W., Morehouse C.A., Brohawn P., Carrasco R.A., Xiao Z., Tice D.A., Higgs B.W., Richman L., Jallal B., Ranade K., Yao Y. 2012. A novel oncogenic role for the miRNA-506-514 cluster in initiating melanocyte transformation and promoting melanoma growth. Oncogene; 31(12): 1558–1570.
• [19]. Sun G., Liu Y., Wang K., Xu Z. 2015. miR-506 regulates breast cancer cell metastasis by targeting IQGAP1. Int. J. Oncol.; 47(5): 1963–1970.
• [20]. Wang Z., Si M., Yang N., Zhang H., Fu Y., Yan K., Zong Y., Zhu N., Wei Y. 2018. MicroRNA-506 suppresses invasiveness and metastasis of human hepatocellular carcinoma cells by targeting IL8. Am. J. Cancer Res.; 8(8): 1586–1594.
• [21]. Arora H., Qureshi R., Park W.Y. 2013. miR-506 regulates epithelial mesenchymal transition in breast cancer cell lines. PLoS One, 8(5): e64273.
• [22]. García-Gutiérrez L., Delgado M. D., León J. 2019. MYC Oncogene Contributions to Release of Cell Cycle Brakes. Genes (Basel); 10(3): 244-254.
• [23]. Budiani D., Mahanani M., Wibowo Y., Probandari A., Prasetyo D., Mudigdo A. 2017. Molecular Therapeutic Potency of Metformin by Targeting p53-Related Molecules in Mutant p53 Colon Cancer Cell Line. Indonesian Journal of Cancer Chemoprevention; 7(1): 17-24.
• [24]. Zhang, J., Li, G., Chen, Y., Fang, L., Guan, C., Bai, F., Ma, M., Lyu, J., Meng, Q. H. 2017. Metformin Inhibits Tumorigenesis and Tumor Growth of Breast Cancer Cells by Upregulating miR-200c but Downregulating AKT2 Expression. Journal of Cancer; 8(10: 1849–1864.
• [25]. Li, Z. H., Zhou, J. H., Chen, S. N., Pan, L., Feng, Y., Luo, M. Q., Li, R. X., Sun, G. L. 2021. MicroRNA-506 has a suppressive effect on the tumorigenesis of nonsmall-cell lung cancer by regulating tubby-like protein 3. Bioengineered; 12(2): 10176–10186.
• [26]. Li, J., Wu, H., Li, W. Yin, L., Guo, S., Xu, X., Ouyang, Y., Zhao, Z., Liu, S., Tian, Y., Tian, Z. Ju, J., Ni, B., Wang, H. 2016. Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling. Oncogene ;35(1): 5501–5514.