RESUMO
AIMS: Secretory clusterin (sCLU) plays an important role in tumor development and cancer progression. However, the molecular mechanisms and physiological functions of sCLU in oral cancer is unclear. We examined the impact of sCLU-mediated autophagy in cell survival and apoptosis inhibition in oral cancer. MAIN METHODS: Immunohistochemical analysis was performed to analyze protein expression in patient samples. Autophagy and mitophagy was studied by immunofluorescence microscopy and Western blot. The gain and loss of function was studied by overexpression of plasmid and siRNA approaches respectively. Cellular protection against nutrient starvation and therapeutic stress by sCLU was studied by cell viability, caspase assay and meta-analysis. KEY FINDINGS: The data from oral cancer patients showed that the expression levels of sCLU, ATG14, ULK1, and PARKIN increased in grade-wise manners. Interestingly, sCLU overexpression promoted autophagy through AMPK/Akt/mTOR signaling pathway leading to cell survival and protection from long exposure serum starvation induced-apoptosis. Additionally, sCLU was demonstrated to interact with ULK1 and inhibition of ULK1 activity by SBI206965 was found to abolish sCLU-induced autophagy indicating critical role of ULK1 in induction of autophagy. Furthermore, sCLU was observed to promote expression of mitophagy-associated proteins in serum starvation conditions to protect cells from nutrient deprivation. The meta-analysis elucidated that high CLU expression is associated with therapy resistance in cancer and we demonstrated that sCLU-mediated mitophagy was revealed to inhibit cell death by cisplatin. SIGNIFICANCE: The present investigation has highlighted the probable implications of the clusterin-induced autophagy in cell survival and inhibition of apoptosis in oral cancer.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Clusterina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Bucais/patologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Apoptose/genética , Autofagia/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Mitofagia/genética , Neoplasias Bucais/genética , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/patologiaRESUMO
Oral cancer is the most common cancer in India. Challenges in the management of oral cancer patients in India include, delay in the presentation with high volume of advanced disease to be handled, affordability of patients and lack economical support especially in the non-governmental institutions and lack of awareness among patients and their relatives. Present study, a retrospective analysis of a prospectively maintained data, portrays the epidemiological features and management of patients with oral cancer presented to a private comprehensive cancer care hospital in the state of Odisha, India. A total of 1049 patients were considered for the analyses, managed between January 2014 and December 2016. Among 1049 patients, 20% (n, 215) were females and 80% (n, 834) were males. Mean age among the present cohort of patients was 50 years with age group 40-55 years being most common. All the patients underwent resection with curative intent and a 1 cm gross resection margins with or without bone and skin. Margin negative resection could be achieved in 82% of patients. Nodal involvement was seen in 36% of patients in the final histopathological assessment. Management of oral cancer patients is a major oncological and reconstructive challenge in India due to the advanced nature of disease at presentation. Inspite of socioeconomic constraints, these patients can be managed even in a private cancer centers with optimum outcomes. This is possible through coordinated team efforts.
