Abstract
S-phase kinase-associated protein2 (Skp2), a proto-oncoprotein, plays an important role in development and progression of human malignancies. Skp2 is frequently overexpressed in many human malignancies. It targets cell cycle progression through ubiquitin mediated degradation of G1-checkpoint CDK inhibitors—p21 (CDKN1A) and p27 (CDKN1B). We investigated the role of Skp2 and its ubiquitin-proteasome pathway in head and neck squamous cell carcinoma (HNSCC) using a panel of cell lines with and without human papillomavirus (HPV+, HPV−). Treatment of HNSCC cell lines with curcumin, a natural compound isolated from rhizomes of the plant Curcuma longa, or transfection of small interfering RNA of Skp2, causes down-regulation of Skp2 with concomitant accumulation of p21 and p27 in HPV+, HPV− cells. Furthermore curcumin inhibits cell viability and induces apoptosis in a dose-dependent manner. Treatment of HPV+ and HPV− cells with curcumin induced apoptosis via mitochondrial pathway and activation of caspases. In addition, treatment of HPV+ and HPV− cell lines with curcumin down-regulated the expression of XIAP, cIAP1, and cIAP2. Interestingly, co-treatment of HNSCC cells with curcumin and cisplatin potentiated inhibition of cell viability and apoptotic effects. Altogether, these data suggest an important function for curcumin, acting as a suppressor of oncoprotein Skp2 in squamous cell carcinoma cells in both HPV+ and HPV− cells; raise the possibility that this agent may have a future therapeutic role in squamous cell carcinoma.
Highlights
Cancer is a complex, life-threatening disease and one of the leading causes of morbidity and mortality around the world [1]
The HNSCCHuman papillomavirus (HPV) status has showed a significant role on prognosis: recent studies revealed that HPV positive (HPV+) patients have a better prognosis as compared to HPV negative (HPV−) patients [8]
We investigated the effects of curcumin on HPV+ and HPV− cell lines focusing on cytotoxicity effects
Summary
Life-threatening disease and one of the leading causes of morbidity and mortality around the world [1]. Head and neck cancer (malignancy of oral cavity, oropharynx, hypopharynx, and larynx) is the sixth most commonly diagnosed and ninth leading cause of cancerrelated death in humans [2, 3]. Use of alcohol and tobacco-related products are the major etiological factors for the malignancies associated with head and neck, and squamous cell carcinoma (HNSCC) is the most common [3]. Human papillomavirus (HPV) has been recognized as an independent risk factor for such tumors, especially if the tumor is located in the oropharynx, where about 50% of tumors harbor the virus [4,5,6,7]. It is well established that HPV+ tumors are distinct tumor entity in regards to carcinogenesis and mutational status as compared to HPV− HNSCC [9]. Due to the better prognosis, HPV+ tumor cells possess intrinsic properties including an increased sensitivity to therapeutic agents, suppressed proliferation rate, and a better immune response due to the presence of the virus
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