Autophagy regulates cisplatin‐induced stemness and chemoresistance via the upregulation of CD44, ABCB1 and ADAM17 in oral squamous cell carcinoma |
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| Authors: | Prajna Paramita Naik Subhadip Mukhopadhyay Prashanta Kumar Panda Niharika Sinha Chandan Kanta Das Rajakishore Mishra Shankargouda Patil Sujit Kumar Bhutia |
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| Affiliation: | 1. Department of Life Science, National Institute of Technology, Rourkela, Odisha, India;2. School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India;3. Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ranchi, Jharkhand, India;4. College of Dentistry, Jazan University, Jazan, Saudi Arabia |
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| Abstract: | Objective We inspected the relevance of CD44, ABCB1 and ADAM17 in OSCC stemness and deciphered the role of autophagy/mitophagy in regulating stemness and chemoresistance. Material and methods A retrospective analysis of CD44, ABCB1 and ADAM17 with respect to the various clinico‐pathological factors and their correlation was analysed in sixty OSCC samples. Furthermore, the stemness and chemoresistance were studied in resistant oral cancer cells using sphere formation assay, flow cytometry and florescence microscopy. The role of autophagy/mitophagy was investigated by transient transfection of siATG14, GFP‐LC3, tF‐LC3, mKeima‐Red‐Mito7 and Western blot analysis of autophagic and mitochondrial proteins. Results In OSCC, high CD44, ABCB1 and ADAM17 expressions were correlated with higher tumour grades and poor differentiation and show significant correlation in their co‐expression. In vitro and OSCC tissue double labelling confirmed that CD44+ cells co‐expresses ABCB1 and ADAM17. Further, cisplatin (CDDP)‐resistant FaDu cells displayed stem‐like features and higher CD44, ABCB1 and ADAM17 expression. Higher autophagic flux and mitophagy were observed in resistant FaDu cells as compared to parental cells, and inhibition of autophagy led to the decrease in stemness, restoration of mitochondrial proteins and reduced expression of CD44, ABCB1 and ADAM17. Conclusion The CD44+/ABCB1+/ADAM17+ expression in OSCC is associated with stemness and chemoresistance. Further, this study highlights the involvement of mitophagy in chemoresistance and autophagic regulation of stemness in OSCC. |
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| Keywords: | ABCB1 ADAM17 autophagy CD44 chemoresistance stemness |
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