Mechanism of metformin action in MCF-7 and MDA-MB-231 human breast cancer cells involves oxidative stress generation, DNA damage, and transforming growth factor β1 induction

Marinello, Poliana Camila; Silva, Thamara Nishida Xavier da; Panis, Carolina; Neves, Amanda Fouto; Machado, Kaliana Larissa; Borges, Fernando H.; Guarnier, Flávia Alessandra; Bernardes, Sara Santos; de-Freitas-Junior, Júlio Cesar Madureira; Morgado‐Díaz, José Andrés; Luiz, Rodrigo Cabral; Cecchini, Rúbens; Cecchini, Alessandra Lourenço

doi:10.1007/s13277-015-4395-x

Cited by 42 publications

(27 citation statements)

References 38 publications

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“…This was also presented in previous studies showing that hyperbaric oxygen treatment lowers proliferation, but does not induce apoptosis in MCF-7 cells (36). Collectively and in agreement with previous studies (39,36) Significant effect of Sirt3 ( a p<0.001) and hyperoxia ( b p<0.001), and their interaction on mitochondrial ROS production is observed (p=0.01).…”

Section: Discussionsupporting

confidence: 92%

De novo expression of transfected sirtuin 3 enhances susceptibility of human MCF-7 breast cancer cells to hyperoxia treatment

Pinterić

Podgorski

Sobočanec

et al. 2018

Free Radical Research

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Sirtuin 3 (Sirt3) has a promising role in cancer tumourigenesis and treatment, but there have been controversies about its role as oncogene or tumour suppressor in different types of cancer. Changes in its expression are associated with the excessive production of reactive oxygen species (ROS), thus contributing to mitochondrial dysfunction and age-related pathologies. Hyperoxic treatment (i.e. generator of ROS) was shown to support some tumourigenic properties, but finally suppresses growth of certain mammary carcinoma cells. Due to strikingly reduced Sirt3 level in many breast cancer cell lines, we aimed to clarify the effect of de novo Sirt3 expression upon hyperoxic treatment in the human MCF-7 breast cancer cells. De novo expression of Sirt3 decreased metabolic activity and cellular growth of MCF-7 cells, reduced expression of proangiogenic and epithelial mesenchymal transition genes, induced metabolic switch from glycolysis to oxidative phosphorylation, and decreased abundance of senescent cells. These effects were enhanced upon hyperoxic treatment: induction of DNA damage and upregulation of p53, with an increase of ROS levels followed by mitochondrial and antioxidant dysfunction, resulted in additional reduction of metabolic activity and inhibition of cellular growth and survival. The mitigation of tumorigenic properties and enhancement of the susceptibility of the MCF-7 breast cancer cells to the hyperoxic treatment upon de novo Sirt3 expression indicates that these factors, individually and in combination, should be further explored in vitro and particularly in vivo, as an adjuvant tumour therapy in breast cancer malignancies.

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Section: Discussionsupporting

confidence: 92%

De novo expression of transfected sirtuin 3 enhances susceptibility of human MCF-7 breast cancer cells to hyperoxia treatment

Pinterić

Podgorski

Sobočanec

et al. 2018

Free Radical Research

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“…Here, we studied the metformin influence on signaling pathways of estrogen‐dependent MCF‐7 breast cancer cells. In the agreement with other observations , we revealed the significant antiproliferative effect of metformin towards MCF‐7 cells in conjunction with the suppression of growth‐related proteins: IκBα, NF‐κB, cyclin D1. Furthermore, we found noticeable decrease in ER expression and activity by metformin action and, in parallel—the decrease in MCF‐7 cells sensitivity to tamoxifen, giving an additional evidence of possible ER signaling involvement into realization of metformin action in breast cancer cells.…”

Section: Discussionsupporting

confidence: 92%

The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling

et al. 2016

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Metformin, a biguanide antidiabetic drug, is used to decrease hyperglycemia in patients with type 2 diabetes. Recently, the epidemiological studies revealed the potential of metformin as an anti-tumor drug for several types of cancer, including breast cancer. Anti-tumor metformin action was found to be mediated, at least in part, via activation of adenosine monophosphate-activated protein kinase (AMPK)-intracellular energy sensor, which inhibits the mammalian target of rapamycin (mTOR) and some other signaling pathways. Nevertheless, some patients can be non-sensitive or resistant to metformin action. Here we analyzed the mechanism of the formation of metformin-resistant phenotype in breast cancer cells and its role in estrogen receptor (ER) regulation. The experiments were performed on the ER-positive MCF-7 breast cancer cells and metformin-resistant MCF-7 subline (MCF-7/M) developed due to long-term metformin treatment. The transcriptional activity of NF-jB and ER was measured by the luciferase reporter gene analysis. The protein expression was determined by immunoblotting (Snail1, (phospho)AMPK, (phospho)IjBa, (phospho)mTOR, cyclin D1, (phospho)Akt and ERa) and immunohistochemical analysis (E-cadherin). We have found that: 1) metformin treatment of MCF-7 cells is accompanied with the stimulation of AMPK and inhibition of growth-related proteins including IjBa, NF-jB, cyclin D1 and ERa; 2) long-term metformin treatment lead to the appearance and progression of cross-resistance to metformin and tamoxifen; the resistant cells are characterized with the unaffected AMPK activity, but the irreversible ER suppression and constitutive activation of Akt/Snail1 signaling; 3) Akt/Snail1 signaling is involved into progression of metformin resistance. The results presented may be considered as the first evidence of the progression of cross-resistance to metformin and Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; EMT, epithelial-mesenchymal transition; ER, estrogen receptor; ERE, estrogen-responsive elements; mTOR, mammalian target of rapamycin 281tamoxifen in breast cancer cells. Importantly, the acquired resistance to both drugs is based on the constitutive activation of Akt/Snail1/E-cadherin signaling that opens new perspectives to overcome the metformin/tamoxifen resistance of breast cancer. V C 2016 IUBMB Life, 68(4): [281][282][283][284][285][286][287][288][289][290][291][292] 2016

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“…Moreover, it was shown to delay the onset of age-related diseases, such as cancer, metabolic syndrome [145], and cognitive disorders [146]. Its mechanism of action is associated with the activation of 5 AMP-activated protein kinase (AMPK) [147,148], inhibition of the mammalian target of rapamycin (mTOR) [149], reduction of DNA damage [150,151], and decreased insulin levels and IGF-1 signaling [152][153][154]. The longevity effect of metformin has not yet been identified in humans, and therefore, its mechanism of action requires further investigation.…”

Section: Metforminmentioning

confidence: 99%

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

et al. 2020

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Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view, as proposed in our previous work. In this review, we discuss the effects of CR on multiple phases of proinflammatory networks and inflammatory signaling pathways to elucidate the basic mechanism underlying aging. Based on studies on senoinflammation and CR, we recognized that senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. These results further support and enhance our understanding of the novel concept of senoinflammation, which is related to the metabolic changes that occur in the aging process. Furthermore, a thorough elucidation of the effect of CR on senoinflammation will reveal key insights and allow possible interventions in aging mechanisms, thus contributing to the development of new therapies focused on improving health and longevity.

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Mechanism of metformin action in MCF-7 and MDA-MB-231 human breast cancer cells involves oxidative stress generation, DNA damage, and transforming growth factor β1 induction

Cited by 42 publications

References 38 publications

De novo expression of transfected sirtuin 3 enhances susceptibility of human MCF-7 breast cancer cells to hyperoxia treatment

De novo expression of transfected sirtuin 3 enhances susceptibility of human MCF-7 breast cancer cells to hyperoxia treatment

The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

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