Exogenous Hydrogen Sulfide Induces A375 Melanoma Cell Apoptosis Through Overactivation of the Unfolded Protein Response

Weiyuan Ma; Xiuwen Zhang; Le Zhuang

doi:10.2147/CCID.S412588

Exogenous Hydrogen Sulfide Induces A375 Melanoma Cell Apoptosis Through Overactivation of the Unfolded Protein Response

Clin Cosmet Investig Dermatol. 2023 Jun 27:16:1641-1651. doi: 10.2147/CCID.S412588. eCollection 2023.

Authors

Weiyuan Ma¹, Xiuwen Zhang², Le Zhuang³

Affiliations

¹ Department of Dermatology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China.
² Department of Dermatology, Weihai Municipal Hospital, Weihai, Shandong Province, People's Republic of China.
³ Department of Dermatology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, People's Republic of China.

Abstract

Purpose: Melanomas are highly malignant and rapidly develop drug resistance due to dysregulated apoptosis. Therefore, pro-apoptotic agents could be effective for the management of melanoma. Hydrogen sulfide is ubiquitous in the body, and exogenous hydrogen sulfide has been reported to show inhibitory and pro-apoptotic effects on cancer cells. However, whether high concentrations of exogenous hydrogen sulfide have pro-apoptotic effects on melanoma and its mechanisms remain unknown. Hence, this study aimed to explore the pro-apoptotic effects and mechanisms of exogenous hydrogen sulfide on the A375 melanoma cell line treated with a hydrogen sulfide donor (NaHS).

Methods: The cell proliferation test, flow cytometric analysis, Hoechst 33258 staining, and Western blotting of B-cell lymphoma 2 and cleaved caspase-3 were used to explore the pro-apoptotic effects of hydrogen sulfide on A375 cells. The transcriptional profile of NaHS-treated A375 cells was further explored via high-throughput sequencing. Western blotting of phosphorylated inositol-requiring enzyme 1α (p-IRE1α), phosphorylated protein kinase R-like ER kinase (p-PERK), phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), C/EBP homologous protein, glucose-regulating protein 78, IRE1α, PERK, and eIF2α was performed to verify the changes in the transcriptional profile.

Results: NaHS inhibited A375 melanoma cell proliferation and induced apoptosis. The endoplasmic reticulum stress unfolded protein response and apoptosis-associated gene expression was upregulated in NaHS-treated A375 melanoma cells. The overactivation of the unfolded protein response and increase in endoplasmic reticulum stress was verified at the protein level.

Conclusion: Treatment with NaHS increased endoplasmic reticulum stress, which triggered the overactivation of the unfolded protein response and ultimately lead to melanoma cell apoptosis. The pro-apoptotic effect of NaHS suggests that it can be explored as a potential therapeutic agent in melanoma.

Keywords: apoptosis; endoplasmic reticulum stress; hydrogen sulfide; melanoma; unfolded proteins response.

Grants and funding

Research reported in this publication was supported by the Traditional Chinese Medicine Science and Technology Project of Shandong Province (No. 2021Q093), the Doctoral Startup Fund of Affiliated Hospital of Weifang Medical University (No. 2021BKQ02), and Shandong Province Natural Science Foundation (No. ZR2020QH138).