Metformin inhibits epithelial‑mesenchymal transition of oral squamous cell carcinoma via the mTOR/HIF‑1α/PKM2/STAT3 pathway

Abstract

Epithelial-mesenchymal transition (EMT) serves an important role in the formation and development of various types of cancer, including oral squamous cell carcinoma (OSCC). Metformin, used for treating type 2 diabetes, has been revealed to exert an anticancer effect in various types of cancer, including liver, breast and colorectal cancer. However, its role in the EMT of OSCC has been rarely reported. Therefore, the present study aimed to investigate the effects of metformin on EMT and to identify its underlying mechanism in OSCC. Firstly, EMT was induced in CAL-27 cells using CoCl 2 . Subsequently, the effects of metformin on cell viability, migration and xenograft growth were evaluated in vitro and in vivo . Reverse transcription-quantitative PCR was performed to detect the expression levels of E-cadherin, vimentin, snail family transcriptional repressor 1, mTOR, hypoxia inducible factor 1α, pyruvate kinase M2 and STAT3. The results demonstrated that metformin abolished CoCl 2 -induced cell proliferation, migration, invasion and EMT. Moreover, metformin reversed EMT in OSCC by inhibiting the mTOR-associated HIF-1α/PKM2/STAT3 signaling pathway. Overall, the present findings characterized a novel mechanism via which metformin modulated EMT in OSCC.

Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection

“…Melatonin is a well-recognized suppressor of HIF-1α under a number of experimental conditions [65][66][67]. While Fig.…”

“…Melatonin is a well-recognized suppressor of HIF-1α under a number of experimental conditions [ 65 – 67 ]. While the mechanism of that suppression is not specifically known [ 68 ], it may be the result of its direct inhibition of the cytosolic oxygen sensor or related to the potent antioxidant activity of the molecule which removes the agents that stabilize HIF-1α, i.e., ROS [ 69 ].…”

Cyclovirobuxine inhibits the progression of clear cell renal cell carcinoma by suppressing the IGFBP3-AKT/STAT3/MAPK-Snail signalling pathway

“…Based on the facts described above, we can conclude that CVB may exert its anti-ccRCC functions by reducing the expression of Snail. Multiple biological signalling cascades participate in the regulation of Snail, including the PI3K/AKT signalling pathway, JAK/STAT3 signalling pathway and MAPK signalling pathway, and these pathways are expected to be attractive therapeutic targets for ccRCC [33][34][35]. In our study, all of these cascades, without exception, were remarkably inhibited by CVB, indicating that the suppression of AKT/STAT3/ MAPK-Snail signalling networks may be the mechanism by which CVB exerts its powerful therapeutic effects on ccRCC.…”

Metformin and colorectal cancer

“…Hallmarks of the EMT include destabilization of adherens junctions, tight junctions and desmosomes, critical structures necessary to maintain epithelial integrity, as well as up regulation of vimentin and α-smooth muscle actin (Lamouille et al, 2014). Recent studies indicated that metformin inhibits EMT in cells derived from different types of cancer including gastric, colon, thyroid, breast, oral and prostate (Esparza-Lopez et al, 2019;Han et al, 2015;Valaee et al, 2017;Wang et al, 2018a;Yin et al, 2021;Zhang and Wang, 2019;Zhang et al, 2014). Several mechanisms had been proposed to explain the inhibitory effect of metformin upon EMT such as down-regulation of transcription factors (SNAIL, TWIST and ZEB), inhibition of PI3K/AKT/mTOR, MAPK, TGFβ, IL-6 and IL-8 signaling and up regulation of miR-381 and miR-200c (Chen et al, 2020).…”