Prajna Paramita Naik1, Subhadip Mukhopadhyay1, Prakash Priyadarshi Praharaj1, Chandra Sekhar Bhol1, Debasna Pritimanjari Panigrahi1, Kewal Kumar Mahapatra1, Srimanta Patra1, Sarbari Saha1, Aditya Kumar Panda2, Krupasindhu Panda3, Subhankar Paul4, Palok Aich5, Samir Kumar Patra6, Sujit Kumar Bhutia7. 1. Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India. 2. Khallikote University, Berhampur, Ganjam, 761008, Odisha, India. 3. Panda Curie Cancer Hospital, Telenga Pentha, Cuttack, 753051, Odisha, India. 4. Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela, 769008, Odisha, India. 5. National Institute of Science Education and Research (NISER), HBNI, Bhipmpur-Padanpur, Jatni, Khurda 752050, Odisha, India. 6. Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India. 7. Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India. Electronic address: sujitb@nitrkl.ac.in.
Abstract
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.
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 cancerpatients 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.
Authors: Christina Cheimonidi; Ioannis N Grivas; Fabiola Sesti; Nadia Kavrochorianou; Despoina D Gianniou; Era Taoufik; Fotis Badounas; Issidora Papassideri; Federica Rizzi; Ourania E Tsitsilonis; Sylva Haralambous; Ioannis P Trougakos Journal: Aging (Albany NY) Date: 2021-03-10 Impact factor: 5.682
Authors: Jun Hong; Selma Maacha; Nataliya Pidkovka; Andreia Bates; Safia N Salaria; Mary K Washington; Abbes Belkhiri Journal: Front Oncol Date: 2022-07-22 Impact factor: 5.738