DNA strand breaks induced by nuclear hijacking of neuronal NOS as an anti-cancer effect of 2-methoxyestradiol

Górska, M.; Kuban–Jankowska, Alicja; Żmijewski, Michał A.; Gammazza, Antonella Marino; Cappello, Francesco; Wnuk, Maciej; Gorzynik, Monika; Rzeszutek, Iwona; Daca, Agnieszka; Lewińska, Anna; Woźniak, Michał

doi:10.18632/oncotarget.3913

Cited by 21 publications

(66 citation statements)

References 97 publications

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“…In addition, CANCER GENOMICS & PROTEOMICS 14: 483-493 (2017) 486 Figure cells were treated with 2-ME alone for 24 h. The cytotoxicity was then determined, and the EC 50 was calculated using CalcuSyn software (Figures 3 and 4). Consistent with our previously published results (18)(19)(20), the EC 50 for 2-ME was determined to be in the range of 1.29×10 -6 M ( Figure 2B). As shown in Figure 2C, L-lactate at the high concentrations of 446 mM and 223 mM decreased the osteosarcoma cell viability with a calculated EC 50 value equal to 224.4 mM.…”

Section: Resultssupporting

confidence: 92%

“…The role of oxidative and nitrosative stress in autophagy has also been widely discussed (58). In our previous studies, we determined that one of anticancer mechanisms of actionof 2-ME is the induction of double-and single-strand breaks due to nuclear hijacking of neuronal nitric oxide synthase (18,19). 2-ME was also shown to induce the DNA damage response pathway (19).…”

Section: Discussionmentioning

confidence: 97%

“…An anticancer mechanism of 2-ME is associated with the induction of mitochondrial oxidative stress resulting in the induction of the mitochondrial apoptotic pathway in cancer cells (38,42). It was previously demonstrated that 2-ME decreased mitochondrial membrane potential due to generation of nitro-oxidative stress leading to cancer cell death (17)(18)(19)(20)(21)43). However, 2-ME also works as an inhibitor of mitochondrial respiration by inhibiting Complex I (39-41).…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies, we determined that one of anticancer mechanisms of actionof 2-ME is the induction of double-and single-strand breaks due to nuclear hijacking of neuronal nitric oxide synthase (18,19). 2-ME was also shown to induce the DNA damage response pathway (19). Moreover, it was suggested that a malfunction of the DNA damage repair system may result in chemoresistance of cancer cells to 2-ME and further progression of the cancer (19).…”

Section: Discussionmentioning

confidence: 99%

“…The analysis was performed as previously described (19). Osteosarcoma 143B cells were seeded onto six-well plates at a density of 3×10 5 cells/well.…”

Section: Cell Migration Assay Kit (Biovendor)mentioning

confidence: 99%

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2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Górska‐Ponikowska

Kuban–Jankowska

Daca

et al. 2017

CGP

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Abstract. Background Cancer cells are traditionally characterized by increased glucose uptake, high rates of aerobic glycolysis, increased lactic acid production, impaired mitochondrial function and decreased extracellular pH. These characteristics are known as the 'Warburg effect' (1-3). The 'Warburg effect' is also observed in cancer-associated fibroblasts and mesenchymal stem cells (1-11), which secrete lactate and ketones into the microenvironment of the tumor. Lactic acid exists as L-and D-optical isomers. In mammals including humans, lactate is present almost entirely as L-lactate (12, 13). Interestingly, a variety of human cancer cell lines and human tumors, including breast, prostate, head, neck, and osteosarcoma cancers, import these metabolites and deliver them to the mitochondrial TCA cycle, thereby promoting ATP generation and cell proliferation (1-14). According to this 'reverse Warburg effect', tumor cells can induce metabolic reprogramming by shuttling lactate as an energy source to neighboring cancer cells, to the adjacent stroma and to vascular endothelial cells (1,14).Tumors contain both aerobic and hypoxic regions that form a metabolic symbiosis that is crucial for tumor cell survival (15, 16). The cancer cells located in the hypoxic regions export lactate, which acidifies the tumor environment; the cells located in the aerobic regions, however, import lactate and utilize it for oxidative phosphorylation (4). Bonuccelli and colleagues (2) suggested that L-lactate metabolism in cancer cells may explain why diabetic patients have an increased risk of cancer development and a tendency towards autophagy/mitophagy in their adipose tissue. An increased tumor L-lactate level strictly correlates with increased metastasis, tumor recurrence and poor outcome (6-9).L-lactate metabolism and the reverse Warburg effect has been clearly established in osteosarcoma cells. It has been demonstrated that the secretion of lactate and ketones by the mesenchymal stem cells drives mitochondrial biogenesis and increases the mitochondrial activity in osteosarcoma cells (1, 483 This article is freely accessible online.Correspondence to: Magdalena Gorska-Ponikowska (MGP),

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…The analysis was performed as previously described (19). Osteosarcoma 143B cells were seeded onto six-well plates at a density of 3×10 5 cells/well.…”

Section: Cell Migration Assay Kit (Biovendor)mentioning

confidence: 99%

See 3 more Smart Citations

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Górska‐Ponikowska

Kuban–Jankowska

Daca

et al. 2017

CGP

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2‐methoxyestradiol impacts on amino acids‐mediated metabolic reprogramming in osteosarcoma cells by its interaction with NMDA receptor

Górska‐Ponikowska

Perricone

Kuban–Jankowska

et al. 2017

Journal Cellular Physiology

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Deregulation of serine and glycine metabolism, have been identified to function as metabolic regulators in supporting tumor cell growth. The role of serine and glycine in regulation of cancer cell proliferation is complicated, dependent on concentrations of amino acids and tissue-specific. D-serine and glycine are coagonists of N-methyl-D-aspartate (NMDA) receptor subunit GRIN1. Importantly, NMDA receptors are widely expressed in cancer cells and play an important role in regulation of cell death, proliferation, and metabolism of numerous malignancies. The aim of the present work was to associate the metabolism of glycine and D-serine with the anticancer activity of 2-methoxyestradiol. 2-methoxyestradiol is a potent anticancer agent but also a physiological 17β- estradiol metabolite. In the study we have chosen two malignant cell lines expressing functional NMDA receptors, that is osteosarcoma 143B and breast cancer MCF7. We used MTS assay, migration assay, flow cytometric analyses, Western blotting and immunoprecipitation techniques as well as molecular modeling studies. We have demonstrated the extensive crosstalk between the deregulated metabolic network and cancer cell signaling. Herein, we observed an anticancer effect of high concentrations of glycine and D-serine in osteosarcoma cells. In contrast, the amino acids when used at low, physiological concentrations induced the proliferation and migration of osteosarcoma cells. Importantly, the pro-cancergogenic effects of both glycine and D-serine where abrogated by the usage of 2-methoxyestradiol at both physiological and pharmacological relevant concentrations. The obtained data confirmed that 2-methoxyestradiol may be a physiological anticancer molecule.

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Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells

et al. 2017

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Plant-derived pentacyclic triterpenotids with multiple biological activities are considered as promising candidates for cancer therapy and prevention. However, their mechanisms of action are not fully understood. In the present study, we have analyzed the effects of low dose treatment (5–20 µM) of ursolic acid (UA) and betulinic acid (BA) on breast cancer cells of different receptor status, namely MCF-7 (ER+, PR+/−, HER2−), MDA-MB-231 (ER−, PR−, HER2−) and SK-BR-3 (ER−, PR−, HER2+). UA-mediated response was more potent than BA-mediated response. Triterpenotids (5–10 µM) caused G0/G1 cell cycle arrest, an increase in p21 levels and SA-beta-galactosidase staining that was accompanied by oxidative stress and DNA damage. UA (20 µM) also diminished AKT signaling that affected glycolysis as judged by decreased levels of HK2, PKM2, ATP and lactate. UA-induced energy stress activated AMPK that resulted in cytotoxic autophagy and apoptosis. UA-mediated elevation in nitric oxide levels and ATM activation may also account for AMPK activation-mediated cytotoxic response. Moreover, UA-promoted apoptosis was associated with decreased pERK1/2 signals and the depolarization of mitochondrial membrane potential. Taken together, we have shown for the first time that UA at low micromolar range may promote its anticancer action by targeting glycolysis in phenotypically distinct breast cancer cells.

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DNA strand breaks induced by nuclear hijacking of neuronal NOS as an anti-cancer effect of 2-methoxyestradiol

Cited by 21 publications

References 97 publications

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

2‐methoxyestradiol impacts on amino acids‐mediated metabolic reprogramming in osteosarcoma cells by its interaction with NMDA receptor

Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells

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