Title |
Demethylation of HIN-1 reverses paclitaxel-resistance of ovarian clear cell carcinoma through the AKT-mTOR signaling pathway
|
---|---|
Published in |
BMC Cancer, October 2015
|
DOI | 10.1186/s12885-015-1744-5 |
Pubmed ID | |
Authors |
Chih-Ming Ho, Chi-Jung Huang, Shih-Hung Huang, Shwu-Fen Chang, Wen-Fang Cheng |
Abstract |
Methylation of HIN-1 is associated with poor outcomes in patients with ovarian clear cell carcinoma (OCCC), which is regarded to be an aggressive, chemo-resistant histological subtype. This study aimed to evaluate whether 5-aza-2-deoxycytidine (5-aza-2-dC) can reverse methylation of the HIN-1 gene to restore chemo-sensitivity of OCCC and the possible mechanism. In vitro flow cytometric analysis and evaluation of caspase-3/7 activity of paclitaxel-sensitive and resistant OCCC cell lines were performed. Methylation status and expression changes of HIN-1 in the OCCC cell lines treated with 5-aza-2-dC were evaluated, and immunohistochemical staining of HIN-1 in OCCC tissues was performed. In vivo tumor growth with or without 5-aza-2-dC treatment was analyzed, and Western blotting of AKT-mTOR signaling-related molecules was performed. G2-M phase arrest was absent in paclitaxel-resistant OCCC cells after treatment with the cytotoxic drug. The caspase activities of the chemo-resistant OCCC cells were lower than those of the chemo-sensitive OCCC cells when treated with paclitaxel. Methylation of HIN-1 was noted in paclitaxel-resistant OCCC cell lines and cancerous tissues. 5-aza-2-dC reversed the methylation of HIN-1, re-activated the expression of HIN-1, and then suppressed the in vivo tumor growth of paclitaxel-resistant OCCC cells. Immunoblotting revealed that phospho-AKT473 and phospho-mTOR were significantly increased in HIN-1-methylated paclitaxel-resistant OCCC cell lines. However, the expressions of phospho-AKT at Ser473 and Thr308 and phospho-mTOR decreased in the OCCC cells with a high expression of HIN-1. Demethylating agents can restore the HIN-1 expression in paclitaxel-resistant OCCC cells through the HIN-1-AKT-mTOR signaling pathway to inhibit tumor growth. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Iran, Islamic Republic of | 1 | 6% |
Unknown | 15 | 94% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Bachelor | 3 | 19% |
Researcher | 3 | 19% |
Student > Master | 2 | 13% |
Student > Ph. D. Student | 2 | 13% |
Unspecified | 1 | 6% |
Other | 2 | 13% |
Unknown | 3 | 19% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 4 | 25% |
Biochemistry, Genetics and Molecular Biology | 3 | 19% |
Agricultural and Biological Sciences | 2 | 13% |
Sports and Recreations | 1 | 6% |
Unspecified | 1 | 6% |
Other | 0 | 0% |
Unknown | 5 | 31% |