Open AccessTIMP-3 Increases the Chemosensitivity of Laryngeal Carcinoma to Cisplatin via Facilitating Mitochondria-Dependent Apoptosis
Author(s) -
Xiaohui Shen,
Xia Gao,
Hui Li,
Yajun Gu,
Junguo Wang
Publication year - 2018
Publication title -
oncology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 57
eISSN - 1555-3906
pISSN - 0965-0407
DOI - 10.3727/096504018x15201099883047
Subject(s) - cisplatin , apoptosis , cancer research , cytochrome c , carcinoma , mitochondrion , biology , downregulation and upregulation , chemotherapy , medicine , pathology , microbiology and biotechnology , biochemistry , gene
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.