Targeting SIRT2 Sensitizes Melanoma Cells to Cisplatin via an EGFR-Dependent Mechanism

Karwaciak, Iwona; Sałkowska, Anna; Karaś, Kaja; Dastych, Jarosław; Ratajewski, Marcin

doi:10.3390/ijms22095034

Cited by 9 publications

(4 citation statements)

References 48 publications

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“…ERK 1/2 is one of the downstream signaling molecules of EGFR pathway. [20] SIRT2 is involved in multidrug-resistant acute myeloid leukemia through extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. [21] Loss of SIRT2 enhanced chemotherapy sensitivity in acute myeloid leukemia.…”

Section: Chemosensitivity By Sirt Inhibitionmentioning

confidence: 99%

The Role of Sirtuin 2 in Chemotherapeutic Resistance

fındık¹

2023

EJMA

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Section: Chemosensitivity By Sirt Inhibitionmentioning

confidence: 99%

The Role of Sirtuin 2 in Chemotherapeutic Resistance

fındık¹

2023

EJMA

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“…When in combination with trichostatin A, etoposide reestablished p53 activity and induced chemoresistance of melanoma cells [ 128 ]. Furthermore, targeting the histone deacetylase SIRT2 sensitized melanoma cells to cisplatin [ 129 ].…”

Section: Epigenetic Modifiers As Therapeutic Adjuvants For Melanoma Patientsmentioning

confidence: 99%

Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

Gracia-Hernandez

Munoz

Villagra

2021

Cancers

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Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma’s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.

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“…Cisplatin has long been recognized as one of the most effective antitumor agents [8]. However, its use is limited by toxic side effects and the development of drug resistance during treatment, making it less applicable in melanoma therapy [9][10][11]. P-terphenyl metabolites are commonly found in macrofungi and are polyaromatic derivatives [12].…”

Section: Introductionmentioning

confidence: 99%

Terphenyllin induces CASP3-dependent apoptosis in A375 cells through upregulation of P53

Wang,

Wu,

et al. 2024

Preprint

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Melanoma, the deadliest form of skin cancer, can develop in any area where melanocytes are present. Currently, platinum-based chemotherapeutic drugs such as cisplatin are commonly used for anti-tumor treatment. However, these drugs often result in significant cytotoxicity, highlighting the need for more effective and less toxic alternatives. Terphenyllin (TER) is a natural compound derived from the coral fungus Aspergillus candidus. Our results demonstrated that TER notably induces apoptosis while exhibiting lower cytotoxicity than does cisplatin at equivalent doses. We observed an upregulation of P53 expression in A375 cells following TER treatment, accompanied by the cleavage of CASP3, GSDME, and PARP1. Upregulated P53 led to increased expression of FAS/BAX and elevated expression of BAX, which prompted the release of cytochrome c from mitochondria to the cytoplasm, ultimately triggering CASP3 cleavage. By knocking out CASP3, TER-induced GSDME cleavage was alleviated and TER-induced A375 cells were shift from apoptosis to necrosis. Additionally, our investigation of the role of GSDME in TER-induced cell death revealed that knockout of GSDME significantly enhanced TER-induced apoptosis and reduced LDH release during induction. Our study demonstrated that TER promotes apoptosis in A375 cells through the P53-BAX-CASP3 pathway. Furthermore, the upregulation of P53 blocks the cell cycle in S-phase by inhibiting CyclinA2 expression. This dual effect eradicates melanoma cells by promoting apoptosis and inhibiting proliferation simultaneously. In summary, our research provides insights into the molecular mechanisms underlying the action of TER on melanoma cells. These findings may have important implications for the development of novel antimelanoma therapeutics.

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Targeting SIRT2 Sensitizes Melanoma Cells to Cisplatin via an EGFR-Dependent Mechanism

Cited by 9 publications

References 48 publications

The Role of Sirtuin 2 in Chemotherapeutic Resistance

The Role of Sirtuin 2 in Chemotherapeutic Resistance

Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

Terphenyllin induces CASP3-dependent apoptosis in A375 cells through upregulation of P53

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