Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR signaling pathways.

Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5' AMPK, thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.

Detailed role of microRNA-mediated regulation of PI3K/AKT axis in human tumors.

The regulation of signal transmission and biological processes, such as cell proliferation, apoptosis, metabolism, migration, and angiogenesis are greatly influenced by the PI3K/AKT signaling pathway. Highly conserved endogenous non-protein-coding RNAs known as microRNAs (miRNAs) have the ability to regulate gene expression by inhibiting mRNA translation or mRNA degradation. MiRNAs serve key role in PI3K/AKT pathway as upstream or downstream target, and aberrant activation of this pathway contributes to the development of cancers. A growing body of research shows that miRNAs can control the PI3K/AKT pathway to control the biological processes within cells. The expression of genes linked to cancers can be controlled by the miRNA/PI3K/AKT axis, which in turn controls the development of cancer. There is also a strong correlation between the expression of miRNAs linked to the PI3K/AKT pathway and numerous clinical traits. Moreover, PI3K/AKT pathway-associated miRNAs are potential biomarkers for cancer diagnosis, therapy, and prognostic evaluation. The role and clinical applications of the PI3K/AKT pathway and miRNA/PI3K/AKT axis in the emergence of cancers are reviewed in this article.

SRF/MRTF-A and liver cirrhosis: Pathologic associations.

Liver cirrhosis results from prolonged and extensive liver fibrosis in which fibrotic tissues replace functional hepatic cells. Chronic liver disease due to various viral, chemical, or metabolic factors initiates hepatic fibrogenesis. Cirrhosis is associated with multiple clinical complications and a poor patient prognosis; therefore, developing novel antifibrotic therapies to prevent cirrhosis is of high priority. Mounting evidence points to the key role of serum response factor (SRF) and myocardin-related transcription factor (MRTF)-A in the pathogenesis of liver fibrosis. SRF is a transcription factor and MRTF-A is a co-activator of SRF and normally resides in the cytoplasm. Upon the induction of fibrotic pathways, MRTF-A translocates into the nucleus and forms the active SRF/MRTF-A complex, leading to the expression of a multitude of fibrotic proteins and components of extracellular matrix. Silencing or inhibiting MRTF-A impedes hepatic stellate cell transdifferentiation into myofibroblasts and slows down the deposition of extracellular matrix in the liver, making it a potential therapeutic target. Here, we review the recent findings regarding the role of the SRF/MRTF-A complex in liver fibrosis and its therapeutic potential for the management of cirrhosis.