Proteomic Analyses of Sirt1-Mediated Cisplatin Resistance in OSCC Cell Line

Abstract

Oral squamous cell carcinoma (OSCC) accounts for about 90% of malignant oral lesions, and is recognized as the third most common cancer in developing nations and the sixth most common cancer worldwide. While chemotherapy remains the primary treatment for both resectable and advanced OSCC, most OSCC are naturally resistant to anticancer drugs, rendering new therapeutic avenues in dire need. Sirt1, a class III histone deacetylase, was linked to cisplatin resistance in several cancer types; however, the underlying mechanism is still unclear. Here, we demonstrated that overexpression of Sirt1 survived OSCC cell line Tca8113 under cisplatin treatment. Notably, BML-210, a chemical inhibitor of class III histone deacetylase, significantly abolished Sirt1-mediated cisplatin resistance in Tca8113 cells. Further, inactivation of endogenic Sirt1 by nicotinamide markedly increased chemo-sensitivity in cisplatin resistant sub-cell line Tca8113/CDDP. Proteomic strategy was applied to profile the differentially expressed proteins between pcDNA3.1-Sirt1- and mock vector-treated Tca8113 cells. Among 54 spots identified, 31 proteins were up-regulated and 23 proteins were down-regulated upon Sirt1 expression. Expression of four proteins with most significant alteration, including Annexin A4, Stathmin, SOD2 and thioredoxin, were validated by both RT-PCR and Western blot. Finally, we showed that Sirt1 could prevent cisplatin-induced ROS accumulation in Tca8113 cells. Our findings are considered as a significant step toward a better understanding of Sirt1-mediated cisplatin resistance.

Annexin A4 and cancer

“…In Sirt1-overexpressed OSCC cell line Tca8113, Sirt1 displayed protective function under cisplatin treatment. Proteomics showed that Anxa4 was overexpressed in pcDNA3.1-Sirt1-transfected Tca8113 cells compared with mock vector [70]. The results indicated that Sirt1 induces cisplatin resistance might via Anxa4 in OSCC.…”

“…Most OSCC are naturally resistant to anticancer drugs, and searching for therapeutic target of OSCC is invaluable [70]. Anxa4 is regulated by Sirt1 in OSCC.…”

“…Anxa4 is regulated by Sirt1 in OSCC. Sirt1, a class III histone deacetylase which could regulate chromatin stability, transcriptional silencing, and DNA damage response, is linked to cisplatin resistance in several cancer types [70]. In Sirt1-overexpressed OSCC cell line Tca8113, Sirt1 displayed protective function under cisplatin treatment.…”

RNA-Mediated Gene Silencing of Nicotinamide N-Methyltransferase Is Associated with Decreased Tumorigenicity in Human Oral Carcinoma Cells

“…Oral squamous cell carcinoma (OSCC) accounts for about 90% of oral malignancies, and is the third most common cancer in developing nations and the sixth most prevalent tumor worldwide [1]. Treatment of OSCC is usually based on surgery or radiation, with or without concomitant chemotherapy.…”

Chronic-Leptin Attenuates Cisplatin Cytotoxicity in MCF-7 Breast Cancer Cell Line

“…In this regard, overexpressed SIRT1 in leptin cells might result in a higher threshold for ROS mediated-apoptosis and explain the resistance to CDDP after leptin exposure. In fact, some works have demonstrated that SIRT1 upregulation contributes to CDDP resistance in association with altered mitochondrial metabolism [65,66]. On the other hand, previous studies from our laboratory and others demonstrated that leptinsignalling pathway induces phosphorylation of STAT3 [9], and it is widely accepted that constitutive activation of the STAT3 pathway confers resistance to CDDP-induced apoptosis in ovarian cancer cells [67,68].…”