Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system

Author:

Ogawa Tatsuo1,Ono Kisho1ORCID,Ryumon Shoji1,Kawai Hotaka2,Nakamura Tomoya1,Umemori Koki1,Yoshida Kunihiro13,Kanemoto Hideka1,Obata Kyoichi1ORCID,Yoshioka Norie1,Okui Tatsuo4ORCID,Okamoto Kuniaki3,Nagatsuka Hitoshi2,Ibaragi Soichiro1ORCID

Affiliation:

1. Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan

2. Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan

3. Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan

4. Department of Oral and Maxillofacial Surgery Shimane University Faculty of Medicine Izumo Shimane Japan

Abstract

AbstractBackgroundCisplatin (CDDP) plays a central role in chemotherapy for head and neck squamous cell carcinoma (HNSCC), but drug resistance in HNSCC chemotherapy remains a problem, and the mechanism of CDDP resistance is unclear. We investigated CDDP‐resistance mechanisms mediated by extracellular vesicles (EVs) and ATPase copper transporting beta (ATP7B) in HNSCC.MethodsWe established CDDP‐resistant sublines of HNSCC cells and verified their ATP7B expression. We used an EV secretion inhibitor (GW4869) and ATP7B short hairpin (sh)RNA transfection to examine the correlation between EV secretion and ATP7B expression.ResultsThe CDDP‐resistant HNSCC sublines showed decreased CDDP sensitivity and increased ATP7B expression. GW4869 suppressed ATP7B expression, and ATP7B shRNA transfection suppressed EV secretion. The suppressions of EV secretion and ATP7B expression both enhanced CDDP's cell‐killing effect.ConclusionsEVs were involved in the ATP7B‐mediated mechanism underlying CDDP resistance. Further clarification of the EV‐induced CDDP‐resistance mechanism may lead to novel therapeutic strategies for HNSCC.

Funder

Wesco Science Foundation

Kawasaki Medical School

Japan Society for the Promotion of Science

Publisher

Wiley

Subject

Otorhinolaryngology

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