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

Xia, Chenglai; Liu, Chang; He, Zhihong; Cai, Yun; Chen, Jinman

doi:10.1186/s13046-020-01627-6

Cited by 44 publications

(40 citation statements)

References 60 publications

(68 reference statements)

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“…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 than naïve cells [25], but blocking NKG2D or MICA/B and ULBP1 does not decrease metformin effect.…”

Section: Discussionsupporting

confidence: 90%

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

Allende-Vega¹,

Marco-Brualla²,

Falvo³

et al. 2021

Preprint

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Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

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Section: Discussionsupporting

confidence: 90%

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

Allende-Vega¹,

Marco-Brualla²,

Falvo³

et al. 2021

Preprint

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“…LDH release assay was performed by using a LDH cytotoxicity assay kit (Yeasen; Shanghai, China) ( 73 ).…”

Section: Methodsmentioning

confidence: 99%

Ferroptosis drives photoreceptor degeneration in mice with defects in all-trans-retinal clearance

Chen

Wang

et al. 2021

Journal of Biological Chemistry

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The death of photoreceptor cells in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1) is closely associated with disruption in all- trans -retinal (atRAL) clearance in neural retina. In this study, we reveal that the overload of atRAL leads to photoreceptor degeneration through activating ferroptosis, a nonapoptotic form of cell death. Ferroptosis of photoreceptor cells induced by atRAL resulted from increased ferrous ion (Fe 2+ ), elevated ACSL4 expression, system Xc − inhibition, and mitochondrial destruction. Fe 2+ overload, tripeptide glutathione (GSH) depletion, and damaged mitochondria in photoreceptor cells exposed to atRAL provoked reactive oxygen species (ROS) production, which, together with ACSL4 activation, promoted lipid peroxidation and thereby evoked ferroptotic cell death. Moreover, exposure of photoreceptor cells to atRAL activated COX2, a well-accepted biomarker for ferroptosis onset. In addition to GSH supplement, inhibiting either Fe 2+ by deferoxamine mesylate salt (DFO) or lipid peroxidation with ferrostatin-1 (Fer-1) protected photoreceptor cells from ferroptosis caused by atRAL. Abca4 −/− Rdh8 −/− mice exhibiting defects in atRAL clearance is an animal model for dry AMD and STGD1. We observed that ferroptosis was indeed present in neural retina of Abca4 −/− Rdh8 −/− mice after light exposure. More importantly, photoreceptor atrophy and ferroptosis in light-exposed Abca4 −/− Rdh8 −/− mice were effectively alleviated by intraperitoneally injected Fer-1, a selective inhibitor of ferroptosis. Our study suggests that ferroptosis is one of the important pathways of photoreceptor cell death in retinopathies arising from excess atRAL accumulation and should be pursued as a novel target for protection against dry AMD and STGD1.

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“…Metformin targets the PI3K/Akt and p53 pathways, and modulates the antitumor immune response in cervical cancer, as reported by Xia et al [ 37 ]. In a study examining the effects of metformin in HeLa cervical cancer and ZR-75-1 breast cancer cell lines, metformin induced HeLa cell death through downregulation of p53 protein [ 51 ].…”

Section: Mechanism Of Metformin In Cervical Cancermentioning

confidence: 79%

Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Chen

Wang

Chen

et al. 2021

Cancers

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Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

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

Cited by 44 publications

References 60 publications

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

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

Ferroptosis drives photoreceptor degeneration in mice with defects in all-trans-retinal clearance

Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

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