Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression

Abstract

Background:Recent studies have shown that the classic hypoglycemic drug metformin inhibits tumor growth; however, the underlying mechanism remains unclear. We previously showed that metformin disrupts the sponge effect of long non-coding RNA MALAT1/miR-142-3p to inhibit cervical cancer cell proliferation. In this study, we interrogated the ability of metformin to modulate the anti-tumor immune response in cervical cancer. Methods:The cell counting kit-8 assay was used to detect the viability of cervical cancer cells. Flow cytometry assays was performed to measure cell apoptosis and cell cycle. Lactate dehydrogenase (LDH) cytotoxicity assay was used to detect NK Cell Cytotoxicity. Relative protein levels were determined by immunoblotting and relative gene levels were determined by quantitative real-time PCR. Tumor Xenograft Modeling was used to evaluate the effect of metformin in vivo.Results: Metformin inhibited cervical cancer cell proliferation, cervical cancer xenograft growth, expression of PCNA, p-PI3K and p-Akt. Moreover metformin induced cervical cancer cell apoptosis and caused cancer cell cycle arrest. In addition, metformin upregulated the expression of DDR-1 and p53 in human cervical cancer cells. Furthermore, metformin also regulated the mRNA and protein expression of MICA and Hsp70 on the surface of human cervical cancer cells via the PI3K/Akt pathway, enhancing NK cell cytotoxicity. Conclusions: In conclusion, our results suggest that metformin may be used as immunopotentiator to inhibit cervical cancer progression and may be considered a viable candidate for combination therapy with immunotherapy.

Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

“…Initially, we believed that metformin sensitizes leukemic cells to NK by induction of stress molecules in target cells. We certainly reproduce previous findings 15 showing that metformin increases expression of stress ligands in multiple cell lines. Our eNK express similar NKG2D levels to naïve cells 25 , but blocking NKG2D or MICA/B and ULBP1 does not decrease metformin effect.…”

“…In vivo metformin inhibits gluconeogenesis from redox-dependent substrates 5 . In vitro and at higher doses, it increases expression of MICA 15 . But, most importantly, metformin inhibits mitochondrial complex I, fructose 1,6-bisphosphatase and CREB and activates AMPK; 5 .…”

Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

“…Initially, we believed that metformin sensitizes leukemic cells to NK by induction of stress molecules in target cells. We certainly reproduce previous ndings 15 showing that metformin increases expression of stress ligands in multiple cell lines. Our eNK express similar NKG2D levels to naïve cells 25 , but blocking NKG2D or MICA/B and ULBP1 does not decrease metformin effect.…”

“…For example, metformin-induced activation of AMPK promotes PD-L1 phosphorylation, resulting in endoplasmic reticulum-associated PD-L1 protein degradation, which increases cytotoxic T-lymphocyte (CTL)-mediated tumor cell death 14 . Metformin-induced metabolic changes can also stress tumor cells and increase expression of the stressinduced ligand MHC Class I Polypeptide-Related Sequence A (MICA) 15 . MICA, and other stress-induced ligands such as MICB and UL16 Binding Proteins (ULBPs), are recognized by activating receptors in CL, e.g.…”

Metformin inhibits pulmonary artery smooth muscle cell proliferation by upregulating p21 via NONRATT015587.2

“…The pathological features of pulmonary hypertension are very similar to tumors, a common feature of which is the abnormal proliferation of cells. Therefore, when selecting the appropriate concentration of MET in vitro, previously reported literature (35)(36)(37)(38) and our previous published article (39) was referred to. Following MET treatment, the expression of NONRATT015587.2 was significantly downregulated (Fig.…”