Melatonin enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44high OSCC cells

Hideo Shigeishi; Sho Yokoyama; Hiroshi Murodumi; Miyuki Sakuma; Shohei Fukada; Satoshi Okuda; Nao Yamakado; Shigehiro Ono; Masaaki Takechi; Kouji Ohta

doi:10.1111/jop.13242

Melatonin enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44^high OSCC cells

J Oral Pathol Med. 2022 Mar;51(3):281-289. doi: 10.1111/jop.13242. Epub 2021 Oct 17.

Authors

Affiliations

¹ Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
² Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

PMID: 34551150
DOI: 10.1111/jop.13242

Abstract

Background: Melatonin is a hormone that is primarily produced in the pineal gland and is involved in wide range of biological functions. However, the impact of melatonin on chemotherapy-induced cell death remains to be elucidated in oral squamous cell carcinoma (OSCC) cells. The objective of this study was to clarify the role of melatonin in cisplatin-induced cytotoxicity in CD44^high OSCC cells.

Methods: CD44^high OSCC cells were cultured on fibronectin-coated hydrogel. A lactate dehydrogenase cytotoxicity assay was performed to evaluate cisplatin-induced cell death. The effect of melatonin on cisplatin-induced cell death and Derlin-1 (DERL1) endoplasmic reticulum membrane protein expression was investigated.

Results: CD44^high OSCC cells exhibited mesenchymal-like features when cultured on fibronectin-coated hydrogel. Mesenchymal-like CD44^high OSCC cells demonstrated strong resistance to cisplatin-induced cell death compared with epithelial-like CD44^high OSCC cells. DERL1 mRNA and DERL1 protein expression levels were significantly higher in mesenchymal-like CD44^high cells compared with epithelial-like CD44^high cells. Cisplatin-induced cell death was significantly enhanced after DERL1 siRNA knockdown, suggesting that DERL1 is involved in resistance to cisplatin-induced cell death. Melatonin significantly inhibited DERL1 expression and enhanced cisplatin-induced cell death in mesenchymal-like CD44^high cells. miR-181c-5p expression was significantly upregulated in the presence of melatonin. Furthermore, melatonin-inhibited DERL1 expression was significantly recovered by miR-181c-5p inhibitor. In addition, melatoninenhanced cisplatin-induced cell death was attenuated by miR-181c-5p inhibitor. These results suggest that melatonin-induced miR-181c-5p enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44^high cells.

Conclusions: Melatonin plays a vital role in promoting cisplatin-induced cytotoxicity in mesenchymal-like CD44^high OSCC cells.

Keywords: CD44; DERL1; cell death; melatonin; oral squamous cell carcinoma.

MeSH terms

Carcinoma, Squamous Cell* / metabolism
Cell Death
Cell Line, Tumor
Cell Proliferation
Cisplatin / pharmacology
Gene Expression Regulation, Neoplastic
Head and Neck Neoplasms* / drug therapy
Head and Neck Neoplasms* / genetics
Humans
Hyaluronan Receptors / metabolism
Melatonin* / pharmacology
MicroRNAs* / genetics
Mouth Neoplasms* / genetics
Squamous Cell Carcinoma of Head and Neck / genetics

Substances

CD44 protein, human
Hyaluronan Receptors
MicroRNAs
Melatonin
Cisplatin

Grants and funding

Grant-in-aid for Scientific Research (C)