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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/jci.insight.143643

CMTM6 drives cisplatin resistance by regulating Wnt signaling through ENO-1/AKT/GSK3β axis

Pallavi Mohapatra,1 Omprakash Shriwas,1 Sibasish Mohanty,1 Arup Ghosh,2 Shuchi Smita,2 Sandeep Rai Kaushik,3 Rakesh Arya,3 Rachna Rath,4 Saroj Das Majumdar,5 Dillip Kumar Muduly,6 Sunil Raghav,2 Ranjan K. Nanda,3 and Rupesh Dash2

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Mohapatra, P. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Shriwas, O. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Mohanty, S. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Ghosh, A. in: JCI | PubMed | Google Scholar |

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Smita, S. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Kaushik, S. in: JCI | PubMed | Google Scholar |

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Arya, R. in: JCI | PubMed | Google Scholar |

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Rath, R. in: JCI | PubMed | Google Scholar |

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Das Majumdar, S. in: JCI | PubMed | Google Scholar |

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Muduly, D. in: JCI | PubMed | Google Scholar |

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Raghav, S. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Nanda, R. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India

2Department of Immunology, Institute of Life Sciences, Bhubaneswar, India

3Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

4Department of Histopathology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, India

5Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, India

6Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, India

Find articles by Dash, R. in: JCI | PubMed | Google Scholar

Published January 12, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.143643.
Copyright © 2021, Mohapatra et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 12, 2021 - Version history
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Abstract

Rewiring tumor cells to undergo drug-induced apoptosis could be a promising way to overcome chemoresistance, therefore identifying causative factors for chemoresistance is of high importance. Global proteome-profiling of sensitive, early and late cisplatin resistant OSCC lines identified CMTM6 as a top ranked up-regulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy-non-responders as compared to responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in ESCC, HNSCC was monitored from Kaplan-Meier-Plot analysis. Stable knockdown of CMTM6 restores cisplatin-mediated cell death in chemoresistant OSCC cell lines. Similarly, upon CMTM6 overexpression in CMTM6KD lines, the cisplatin resistant phenotype was efficiently rescued. The patient-derived cell xenograft model of chemoresistant OSCC displayed CMTM6 depletion restored the cisplatin-induced cell death and tumor burden significantly. The transcriptome analysis of CMTM6KD and control chemoresistant cells depicted enrichment of Wnt-signaling pathway. Mechanistically, we demonstrated that CMTM6 interaction with membrane bound Enolase-1 stabilized its expression, leading to AKT-GSK3β mediated activation of Wnt-signaling. CMTM6 has been identified as a stabilizer of PD-L1 thereby facilitates immune evasion by tumor cells. As CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it can be an important therapeutic target for therapy resistant OSCC.

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