SIRT2 Contributes to the Resistance of Melanoma Cells to the Multikinase Inhibitor Dasatinib

Karwaciak, Iwona; Sałkowska, Anna; Karaś, Kaja; Sobalska‐Kwapis, Marta; Walczak‐Drzewiecka, Aurelia; Pułaski, Łukasz; Strapagiel, Dominik; Dastych, Jarosław; Ratajewski, Marcin

doi:10.3390/cancers11050673

Cited by 26 publications

(38 citation statements)

References 94 publications

(118 reference statements)

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“…Karwaciak and colleagues [ 68 ] demonstrated that the SIRT2 inhibitor AC-93253 inhibits the expression of genes involved in the progression and chemoresistance of melanoma, influencing proliferation and apoptosis. They also demonstrated that SIRT2 inhibition makes melanoma cells sensible to dasatinib [ 69 ]. Furthermore, SIRT1&2 knockdown inhibits proliferation and decreases colony formation in melanoma cells [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide inhibits melanoma in vitro and in vivo

Scatozza

Moschella

D’Arcangelo

et al. 2020

J Exp Clin Cancer Res

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Background Even though new therapies are available against melanoma, novel approaches are needed to overcome resistance and high-toxicity issues. In the present study the anti-melanoma activity of Nicotinamide (NAM), the amide form of Niacin, was assessed in vitro and in vivo. Methods Human (A375, SK-MEL-28) and mouse (B16-F10) melanoma cell lines were used for in vitro investigations. Viability, cell-death, cell-cycle distribution, apoptosis, Nicotinamide Adenine Dinucleotide+ (NAD+), Adenosine Triphosphate (ATP), and Reactive Oxygen Species (ROS) levels were measured after NAM treatment. NAM anti-SIRT2 activity was tested in vitro; SIRT2 expression level was investigated by in silico transcriptomic analyses. Melanoma growth in vivo was measured in thirty-five C57BL/6 mice injected subcutaneously with B16-F10 melanoma cells and treated intraperitoneally with NAM. Interferon (IFN)-γ-secreting murine cells were counted with ELISPOT assay. Cytokine/chemokine plasmatic levels were measured by xMAP technology. Niacin receptors expression in human melanoma samples was also investigated by in silico transcriptomic analyses. Results NAM reduced up to 90% melanoma cell number and induced: i) accumulation in G1-phase (40% increase), ii) reduction in S- and G2-phase (about 50% decrease), iii) a 10-fold increase of cell-death and 2.5-fold increase of apoptosis in sub-G1 phase, iv) a significant increase of NAD+, ATP, and ROS levels, v) a strong inhibition of SIRT2 activity in vitro. NAM significantly delayed tumor growth in vivo (p ≤ 0.0005) and improved survival of melanoma-bearing mice (p ≤ 0.0001). About 3-fold increase (p ≤ 0.05) of Interferon-gamma (IFN-γ) producing cells was observed in NAM treated mice. The plasmatic expression levels of 6 cytokines (namely: Interleukin 5 (IL-5), Eotaxin, Interleukin 12 (p40) (IL12(p40)), Interleukin 3 (IL-3), Interleukin 10 (IL-10) and Regulated on Activation Normal T Expressed and Secreted (RANTES) were significantly changed in the blood of NAM treated mice, suggesting a key role of the immune response. The observed inhibitory effect of NAM on SIRT2 enzymatic activity confirmed previous evidence; we show here that SIRT2 expression is significantly increased in melanoma and inversely related to melanoma-patients survival. Finally, we show for the first time that the expression levels of Niacin receptors HCAR2 and HCAR3 is almost abolished in human melanoma samples. Conclusion NAM shows a relevant anti-melanoma activity in vitro and in vivo and is a suitable candidate for further clinical investigations.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide inhibits melanoma in vitro and in vivo

Scatozza

Moschella

D’Arcangelo

et al. 2020

J Exp Clin Cancer Res

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“…To our knowledge, for the first time, we have demonstrated that SIRT2 could contribute to cisplatin sensitivity. Previously, SIRT2 was reported to increase the resistance of anticancer drugs in melanoma and nasopharyngeal carcinoma [ 27 , 41 ]. These results seem contradictory but also make great sense in view of the dual tumor suppressive and oncogenic role of SIRT2 in cancer.…”

Section: Discussionmentioning

confidence: 99%

ROS-Induced SIRT2 Upregulation Contributes to Cisplatin Sensitivity in Ovarian Cancer

Wang

Kim

et al. 2020

Antioxidants

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Cisplatin resistance remains a significant obstacle for improving the clinical outcome of ovarian cancer patients. Recent studies have demonstrated that cisplatin is an important inducer of intracellullar reactive oxygen species (ROS), triggering cancer cell death. Sirtuin 2 (SIRT2), a member of class III NAD+ dependent histone deacetylases (HDACs), has been reported to be involved in regulating cancer hallmarks including drug response. In this study, we aimed to identify the role of SIRT2 in oxidative stress and cisplatin response in cancer. Two ovarian cancer cell lines featuring different sensitivities to cisplatin were used in this study. We found different expression patterns of SIRT2 in cisplatin-sensitive (A2780/S) and cisplatin-resistant (A2780/CP) cancer cells with cisplatin treatment, where SIRT2 expression was augmented only in A2780/S cells. Furthermore, cisplatin-induced ROS generation was responsible for the upregulation of SIRT2 in A2780/S cells, whereas overexpression of SIRT2 significantly enhanced the sensitivity of cisplatin-resistant counterpart cells to cisplatin. Our study proposes that targeting SIRT2 may provide new strategies to potentiate platinum-based chemotherapy in ovarian cancer patients.

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“…As an example for the latter, inhibition of SIRT1 by the up-regulation of miR-211-5p was associated with the induction of apoptosis in breast cancer cells (91). Inhibition of SIRT2 has been confirmed to induce the susceptibility of melanoma cell to the multikinase inhibitor dasatinib (92).…”

Section: Special Aspects Of Novel Epigenetic and Metabolic Therapeutimentioning

confidence: 93%

Impact of Sirtuin Enzymes on the Altered Metabolic Phenotype of Malignantly Transformed Cells

Gaál

Csernoch

2020

Front. Oncol.

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Sirtuins compose a unique collection of histone deacetylase enzymes that have a wide variety of enzymatic activities and regulate diverse cell functions such as cellular metabolism, longevity and energy homeostasis, mitochondrial function, and biogenesis. Impaired sirtuin functions or alterations of their expression levels may result in several pathological conditions and contribute to the altered metabolic phenotype of malignantly transformed cells in a significant manner. In the twenty-first century, principles of personalized anticancer treatment need to involve not only the evaluation of changes of the genetic material, but also the mapping of epigenetic and metabolic alterations, to both of which the contribution of sirtuin enzymes is fundamental. Since sirtuins are central players in the maintenance of cellular energy and metabolic homeostasis, they are key elements in the development of metabolic transformation of cancer cells referred to as the Warburg effect. Although its most well-known features are enhanced glycolysis and excessive lactate production, Warburg effect has several aspects involving both carbohydrate, lipid, and amino acid metabolism, among which different tumor types have different preferences. Therefore, energy supply of cancer cells can be impaired by a growing number of antimetabolite agents, for which appropriate vectors are strongly needed. However, data are controversial about their tumor suppressor or oncogenic properties, the biological effects of sirtuin enzymes strongly depend on the tissue microenvironment (TME) in which they are expressed. Immune cells are regarded as key players of TME. Sirtuins regulate the survival, activation, metabolism, and mitochondrial function of these cells, therefore, they are not only single elements, but key regulators of the network that determines anticancer immunity. Altered metabolism of tumor cells induces changes in the gene expression pattern of cells in TME, due to altered concentrations of metabolite cofactors of epigenetic modifiers including sirtuins. In summary, epigenetic and metabolic alterations in malignant diseases are influenced by sirtuins in a significant manner, and should be treated in a personalized approach. Since they often develop in early stages of cancer, broad examination of these alterations is required at time of the diagnosis in order to provide a personalized combination of distinct therapeutic agents.

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SIRT2 Contributes to the Resistance of Melanoma Cells to the Multikinase Inhibitor Dasatinib

Cited by 26 publications

References 94 publications

Nicotinamide inhibits melanoma in vitro and in vivo

Nicotinamide inhibits melanoma in vitro and in vivo

ROS-Induced SIRT2 Upregulation Contributes to Cisplatin Sensitivity in Ovarian Cancer

Impact of Sirtuin Enzymes on the Altered Metabolic Phenotype of Malignantly Transformed Cells

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