Abstract
Metformin is a commonly prescribed antihyperglycemic drug, and has been investigated in vivo and in vitro for its effect to improve the comorbidity of diabetes and various types of cancers. Several studies investigated the therapeutic mechanisms of metformin on cancer cells, but the exact mechanism of metformin’s effect on the proteomic pathways of cancer cells is yet to be further investigated. The main objective of our research line is to discover safe and alternative therapeutic options for breast cancer, we aimed in this study to design a novel “bottom up proteomics workflow” in which proteins were first broken into peptides to reveal their identity, then the proteomes were precisely evaluated using spectrometry analysis. In our study, metformin suppressed cell proliferation and induced apoptosis in human breast carcinoma cell line MCF-7 with minimal toxicity to normal breast epithelial cells MCF-10. Metformin induced apoptosis by arresting cells in G1 phase as evaluated by flow cytometric analysis. Moreover, The G1 phase arrest for the MCF-7 has been confirmed by increased expression levels of p21 and reduction in cyclin D1 level. Additionally, metformin increased the expression levels of p53, Bax, Bad while it reduced expression levels of Akt, Bcl-2, and Mdm2. The study employed a serviceable strategy that investigates metformin-dependent changes in the proteome using a literature-derived network. The protein extracts of the treated and untreated cell lines were analyzed employing proteomic approaches; the findings conveyed a proposed mechanism of the effectual tactics of metformin on breast cancer cells. Metformin proposed an antibreast cancer effect through the examination of the proteomic pathways upon the MCF-7 and MCF-10A exposure to the drug. Our findings proposed prolific proteomic changes that revealed the therapeutic mechanisms of metformin on breast cancer cells upon their exposure. In conclusion, the reported proteomic pathways lead to increase the understanding of breast cancer prognosis and permit future studies to examine the effect of metformin on the proteomic pathways against other types of cancers. Finally, it suggests the possibility to develop further therapeutic generations of metformin with increased anticancer effect through targeting specific proteomes.
Highlights
Breast cancer is more globally prevalent in females’ communities and classified as the second death-leading type of cancer worldwide after lung cancer [1,2,3,4]
We investigated the possible mechanisms of metformin’s effect on breast epithelial adenocarcinoma cells (MCF-7) in comparison with normal healthy cells (MCF-10A)
This aimed to study protein targets resulted from metformin treatment in order to examine the possible signaling pathways, which may elucidate some explanations behind the beneficial effect of metformin on breast adenocarcinoma
Summary
Breast cancer is more globally prevalent in females’ communities and classified as the second death-leading type of cancer worldwide after lung cancer [1,2,3,4]. Metformin Targets Breast Cancer or lifestyle risk factors [2]. Despite the available treatment protocols, cancer patients remain at a higher risk of disease recurrence or secondary disease development, early detection and risk factors avoidance remain essential strategies for breast cancer prevention [3, 4]. The available treatment options of chemotherapy, mastectomy, radiation, and hormonal therapy remain to be the most commonly used therapeutic strategies to increase the survival rates of breast cancer patients [5]. Metformin has been found to improve the comorbidity survival for diabetic-cancer patients, in particular breast cancer. Metformin treatment is widely prescribed for type two diabetes and has been used off-label for the treatment of polycystic ovarian syndrome [7]; metformin was found to be associated with decreased incidence of various types of cancers such as breast, pancreas, hepatocellular carcinoma, colorectal, and prostate cancers [8]
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