Original Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Oct 28, 2013; 19(40): 6814-6824
Published online Oct 28, 2013. doi: 10.3748/wjg.v19.i40.6814
Curcumin cytotoxicity is enhanced by PTEN disruption in colorectal cancer cells
Lin Chen, Wen-Feng Li, Hong-Xiao Wang, Hai-Na Zhao, Jia-Jia Tang, Chang-Jie Wu, Li-Ting Lu, Wan-Qin Liao, Xin-Cheng Lu
Lin Chen, Hong-Xiao Wang, Hai-Na Zhao, Jia-Jia Tang, Chang-Jie Wu, Li-Ting Lu, Wan-Qin Liao, Xin-Cheng Lu, Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
Wen-Feng Li, Department of Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
Author contributions: Chen L and Li WF performed the main experiments, and contributed equally to this work; Tang JJ, Wang HX, Wu CJ and Zhao HN performed part of the experiments; Lu LT provided technical assistance; Liao WQ and Lu XC designed the research and wrote the manuscript.
Supported by The National Natural Science Foundation of China, No. 81101472 to Liao WQ; No. 31071086 to Lu XC
Correspondence to: Xin-Cheng Lu, Professor, Institute of Genomic Medicine, Wenzhou Medical University, No. 270 Xueyuanxi Road, Wenzhou 325027, Zhejiang Province, China. xinchenglu@yahoo.com
Telephone: +86-577-88831350 Fax: +86-577-88831359
Received: July 3, 2013
Revised: September 2, 2013
Accepted: September 15, 2013
Published online: October 28, 2013
Processing time: 132 Days and 14.9 Hours
Abstract

AIM: To investigate the effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency on the cytotoxicity of chemotherapeutic agents toward colorectal cancer cells.

METHODS: PTEN-deficient colorectal cancer (CRC) cells were generated by human somatic cell gene targeting using the adeno-associated virus system. The cytotoxic effects of compounds including curcumin, 5-fluorouracil (5-FU), dihydroartemisinin (DHA), irinotecan (CPT-11) and oxaliplatin (OXA) on cancer cells were determined using the MTT assay. Enhanced cytotoxicity of curcumin in PTEN-deficient CRC cells was observed, and this was confirmed using clonogenic assays. Apoptosis and cell cycle progression were analyzed by flow cytometry. Levels of apoptosis and cell cycle-related proteins were examined by Western blotting.

RESULTS: We developed an isogenic set of CRC cell lines that differed only in their PTEN status. Using this set of cell lines, we found that disruption of the PTEN gene had no effect on the sensitivity of CRC cells to 5-FU, CPT-11, DHA, or OXA, whereas PTEN disruption increased the sensitivity of CRC cells to curcumin. Loss of PTEN did not alter the curcumin-induced apoptosis in CRC cells. However, PTEN deficiency led to an altered pattern of curcumin-mediated cell cycle arrest. In HCT116 PTEN+/+ cells, curcumin caused a G2/M phase arrest, whereas it caused a G0/G1 phase arrest in HCT116 PTEN-/- cells. Levels of cell cycle-related proteins were consistent with these respective patterns of cell cycle arrest.

CONCLUSION: Curcumin shows enhanced cytotoxicity toward PTEN-deficient cancer cells, suggesting that it might be a potential chemotherapeutic agent for cancers harboring PTEN mutations.

Keywords: Phosphatase and tensin homolog deleted on chromosome 10; Curcumin; Chemotherapeutic agents; Cell cycle; AKT signaling

Core tip: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) mutations lead to cancer progression and drug resistance. Chemotherapeutic agents with enhanced effectiveness against cancers with PTEN mutations are urgently required. In this study, we generated an isogenic set of human colorectal cancer cell lines that differed only in their PTEN status. We found that curcumin showed enhanced cytotoxicity in cancer cells deficient in PTEN. Importantly, PTEN deficiency led to an alteration in the pattern of curcumin-induced cell cycle arrest, which was associated with the PTEN/AKT/p21 pathway. Our findings suggest that curcumin is a potential chemotherapeutic agent for PTEN-mutant cancers.