Open Access

ARTICLE

TIMP-3 Increases the Chemosensitivity of Laryngeal Carcinoma to Cisplatin via Facilitating Mitochondria-Dependent Apoptosis

Xiaohui Shen, Xia Gao, Hui Li, Yajun Gu, Junguo Wang

Department of Otolaryngology Head and Neck, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P.R. China

Oncology Research 2019, 27(1), 73-80. https://doi.org/10.3727/096504018X15201099883047

Abstract

Laryngeal carcinoma is a type of head and neck carcinoma with a high incidence and mortality. Chemotherapy treatments of human laryngeal carcinoma may fail due to the development of chemoresistance. Tissue inhibitor of metalloproteinase 3 (TIMP-3) has been shown to be implicated in a number of pathological processes typical for cancer. The present study aims to investigate the involvement of TIMP-3 in the chemoresistance of laryngeal carcinoma. We showed that TIMP-3 expression was significantly decreased in chemoresistant laryngeal carcinoma tissues compared with chemosensitivity tissues. Patients with low TIMP-3 expression exhibited poorer overall survival than those with high TIMP-3 expression. Moreover, cisplatin-resistant Hep-2 cells (Hep-2/R) were associated with the inhibition of mitochondrial membrane potential (MtMP) depolarization after cisplatin challenge. In addition, cisplatin resulted in a more pronounced mitochondrial cytochrome c release into the cytoplasm in Hep-2 cells than in their resistant variants. Overexpression of TIMP-3 by an adenovirus encoding TIMP-3 cDNA remarkably enhanced cisplatin-induced apoptosis, cytochrome c release, and caspase activation in Hep-2/R cells, thereby sensitizing cancer cells to cisplatin. On the other hand, downregulation of TIMP-3 markedly inhibited cisplatin-induced apoptosis in Hep-2 cells through attenuating mitochondria-dependent pathway activation. Taken together, these results demonstrate that decreased TIMP-3 expression may contribute to cisplatin resistance via inhibition of mitochondria-dependent apoptosis, indicating that forced TIMP-3 expression may be a useful strategy to improve the efficacy of cisplatin to treat laryngeal carcinoma.

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