14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules
- 221 Downloads
Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used in chemoradiation for unresectable ESCC patients. However, the treatment efficacy is diminished in patients with established cisplatin resistance. To understand the mechanism leading to the development of cisplatin resistance in ESCC, we compared the proteomes from a cisplatin-resistant HKESC-2R cell line with its parental-sensitive counterpart HKESC-2 to identify key molecule involved in this process. Mass spectrometry analysis detected 14-3-3σ as the most abundant molecule expressed exclusively in HKESC-2R cells, while western blot result further validated it to be highly expressed in HKESC-2R cells when compared to HKESC-2 cells. Ectopic expression of 14-3-3σ increased cisplatin resistance in HKESC-2 cells, while its suppression sensitized SLMT-1 cells to cisplatin. Among the molecules involved in drug detoxification, drug transportation, and DNA repair, the examined DNA repair molecules HMGB1 and XPA were found to be highly expressed in HKESC-2R cells with high 14-3-3σ expression. Subsequent manipulation of 14-3-3σ by both overexpression and knockdown approaches concurrently altered the expression of HMGB1 and XPA. 14-3-3σ, HMGB1, and XPA were preferentially expressed in cisplatin-resistant SLMT-1 cells when compared to those more sensitive to cisplatin. In ESCC patients with poor response to cisplatin-based chemoradiation, their pre-treatment tumors expressed higher expression of HMGB1 than those with response to such treatment. In summary, our results demonstrate that 14-3-3σ induces cisplatin resistance in ESCC cells and that 14-3-3σ-mediated cisplatin resistance involves DNA repair molecules HMGB1 and XPA. Results from this study provide evidences for further work in researching the potential use of 14-3-3σ and DNA repair molecules HMGB1 and XPA as biomarkers and therapeutic targets for ESCC.
Keywords14-3-3σ HMGB1 XPA Cisplatin Esophageal squamous cell carcinoma
This project was supported by Small Project Funding, The University of Hong Kong and Special Equipment Grant from the University Grants Committee of the Hong Kong Special Administrative Region, China (SEG_HKU02).
Conflicts of interest
- 6.Du P, Zhang X, Liu H, Chen L. Lentivirus-Mediated RNAi Silencing Targeting ERCC1 Reverses Cisplatin Resistance in Cisplatin-Resistant Ovarian Carcinoma Cell Line. DNA Cell Biol. 2015;in press.Google Scholar
- 8.Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015;16:436–46.CrossRefPubMedGoogle Scholar
- 11.Chen HH, Chen WC, Liang ZD, Tsai WB, Long Y, Aiba I et al. Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy. Expert Opin Ther Targets. 2015;1-11.Google Scholar
- 31.Liu Y, Prasad R, Wilson SH. HMGB1: roles in base excision repair and related function. Biochim Biophys Acta. 1799;2010:119–30.Google Scholar