Screening Novel Molecular Targets of Metformin in Breast Cancer by Proteomic Approach

Al-Zaidan, Lobna; Ruz, Rasha Abu El; Malki, Ahmed

doi:10.3389/fpubh.2017.00277

Cited by 18 publications

(9 citation statements)

References 71 publications

(87 reference statements)

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“…Its hyper-activation can lead to excessive tumor cell proliferation, inhibition of apoptosis, angiogenesis, invasion and metastasis (40)(41)(42). For our part, we suggest that MET treatment may play a noticeable role in modulating cell signaling activation related to PI3K/Akt/mTOR pathways in breast cancer cells, that corroborates recent reports (43,44).…”

Section: Discussionsupporting

confidence: 90%

Phenotypic functional activities of monocyte change during crosstalk with breast cancer cell and enhancing effect of metformin of IFN-γ-associated antitumor cytokine production

Dahmani

Addou-Klouche

Gizard

et al. 2020

Preprint

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Background: Immune activities of monocytes (MOs) can be altered within the microenvironment of solid malignancies, including breast cancer. Metformin (1,1dimethylbiguanide hydrochloride, MET), has been shown to decrease tumor cell proliferation, but its effects have yet to be explored with respect to the crosstalk between monocytes and breast cancer cells. Here, we investigated the effects of MET on overall phenotypic functional activities of autologous MOs during the interplay with primary breast cancer cells. Methods:Human primary breast cancer cells were either cultured alone or co-cultured with autologous MOs before treatment with MET.Results: MET downregulated both breast cancer cell proliferation and the ratio of phosphorylated Akt (p-Akt)-to-Akt in breast cancer cells. Additionally, we observed that, in the absence of MET treatment, the levels of LDH-based cytotoxicity, catalase, intracellular free calcium ions (i fCa 2+ ), IL-10 and arginase activity were significantly reduced in co-cultures compared to those of MOs cultivated alone whereas levels of iNOS were significantly increased (for all comparisons, p < 0.05). In contrast, MET upregulated breast cancer cell LDH-based cytotoxicity levels when co-cultured with MO. MET also induced upregulation of both the inducible enzymatic activity of nitric oxide synthase (iNOS) and arginase activity in MO cells and co-culture systems, although these differences did not reach significant levels for iNOS activity (p > 0.05). MET greatly decreased phagocytic activity in isolated MOs while inducing a robust increase of catalase activity in co-culture systems and of superoxide dismutase (SOD) activity in MOs, but not in MOs co-cultured with breast cancer cells. MET strongly upregulated the levels of ifCa 2+ in co-culture systems and IFN-γ production in both isolated MOs and co-culture systems. Moreover, MET treatment markedly downregulated IL-10 production in MOs, while inducing a slight increase in co-cultures (p > 0.05). Conclusions: Our results show that the phenotypic functional activities of MOs change when co-cultured with primary human breast cancer cells. Furthermore, treatment with MET induced enhancing effects on the production of antitumor cytokine IFN-γ and ifCa 2+ , as well as cytotoxicity during breast cancer cell-MO crosstalk. Keywords: Akt activation; metformin; monocyte/primary human breast cancer cell crosstalk; monocyte phenotypic functional activity changes; primary breast cancer cell proliferation and viability; MO IFN-γ-associated anti-tumor activity

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Section: Discussionsupporting

confidence: 90%

Phenotypic functional activities of monocyte change during crosstalk with breast cancer cell and enhancing effect of metformin of IFN-γ-associated antitumor cytokine production

Dahmani

Addou-Klouche

Gizard

et al. 2020

Preprint

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“…2f, metformin may reduce cisplatin resistance induced by TNBC-EVs in normal tissues via RAD51. In addition, it was reported that metformin selectively targeted cancer stem cells and also induced apoptosis in human breast carcinoma cell line MCF-7 with minimal toxicity to MCF10A [52, 53]. Furthermore, metformin prevented normal cell apoptosis against cisplatin-induced ototoxicity and nephrotoxicity in auditory cell and tubular cell [54].…”

Section: Discussionmentioning

confidence: 99%

Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51

et al. 2019

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Background: Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. Methods: Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. Results: Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. Conclusions: Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.

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“…For our part, at the concentration of MET used (2.5 mM) we found a modest and non significant reduction of the PI3K/Akt activation in breast cancer cells. However, several studies reported that metformin reduced the survival and proliferation rate of breast cancer cells through the inhibition of PI3K/Akt signaling pathway [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin partially reverses the inhibitory effect of co-culture with ER-/PR-/HER2+ breast cancer cells on biomarkers of monocyte antitumor activity

et al. 2020

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Background Immune activities of monocytes (MOs) can be altered within the microenvironment of solid malignancies, including breast cancer. Metformin (1,1-dimethylbiguanide hydrochloride, MET), has been shown to decrease tumor cell proliferation, but its effects have yet to be explored with respect to MOs (monocytes) activity during their crosstalk with breast cancer cells. Here, we investigated the effects of MET on overall phenotypic functional activities, including cellular immunometabolism and protective redox signaling based-biomarkers, intracellular free calcium ions ( if Ca 2+ ), phagocytosis and co-operative cytokines (IFN-γ and IL-10) of autologous MOs before and during their interplay with primary ER - /PR - /HER2 + breast cancer cells. Methods Human primary breast cancer cells were either cultured alone or co-cultured with autologous MOs before treatment with MET. Results MET downregulated breast cancer cell proliferation and phagocytosis, while having no significant effect on the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, we observed that, in the absence of MET treatment, the levels of lactate dehydrogenase (LDH)-based cytotoxicity, catalase, if Ca 2+ , IL-10 and arginase activity were significantly reduced in co-cultures compared to levels in MOs cultured alone whereas levels of inducible nitric oxide synthase (iNOS) activity were significantly increased. In contrast, MET treatment reduced the effects measured in co-culture on the levels of LDH-based cytotoxicity, arginase activity, catalase, if Ca 2+ , and IFN-γ. MET also induced upregulation of both iNOS and arginase in MO cells, although the increase did not reach significant difference for iNOS activity. Moreover, MET induced a robust increase of superoxide dismutase (SOD) activity in MOs, but not in MOs co-cultured with breast cancer cells. Furthermore, MET markedly upregulated the levels of IFN-γ production and downregulated those of IL-10 in isolated MOs, while inducing a slight opposing up-regulation of IL-10 production in co-cultures. Conclusions Our results show that the biomarkers of phenotypic functional activities of MOs are modified after co-culturing with primary human breast cancer cells. Treatment of co-cultures with MET resulted in increased release of antitumor cytokine IFN-γ and if Ca 2+ , and increased cell necrosis during breast cancer cells-MOs crosstalk.

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Screening Novel Molecular Targets of Metformin in Breast Cancer by Proteomic Approach

Cited by 18 publications

References 71 publications

Phenotypic functional activities of monocyte change during crosstalk with breast cancer cell and enhancing effect of metformin of IFN-γ-associated antitumor cytokine production

Phenotypic functional activities of monocyte change during crosstalk with breast cancer cell and enhancing effect of metformin of IFN-γ-associated antitumor cytokine production

Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51

Metformin partially reverses the inhibitory effect of co-culture with ER-/PR-/HER2+ breast cancer cells on biomarkers of monocyte antitumor activity

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