Chemotherapeutic resistance of head and neck squamous cell carcinoma is mediated by EpCAM induction driven by IL-6/p62 associated Nrf2-antioxidant pathway activation
| Autor: | Nabila Chowdhury, Sonam Akther, Lutfur Rahman, Syed S. Islam, S. M. Ikram Hossain, Junayed Nayeem, Muhammad Mohsin Hossain, Mohammad Z. Rahman, Srikanta Chowdhury, Arfina Chowdhury, Rajib Shil, Tahmina Banu, Rashed R Parag, Afrin Sultana, Ali Asgar Chowdhury, Chandsultana Jerin, Shafiqul Islam, Reaz Mahmud, Herman Yeger, Jannatul Aklima, Shammy Bithy, Muhammad I. Rashid, Muhammad N. Hasan, Shabnam B. Basher, Abul Hasan, Sunanda Baidya, Mizanur Rahman, Abu Shadat M. Noman, Sharmin A. Sumi, Walid A. Farhat, Ayesha Siddiqua, Afsana Shirin |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research NF-E2-Related Factor 2 Immunology SOD1 environment and public health Article Antioxidants 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine SOX2 Cell Line Tumor medicine Gene silencing Humans lcsh:QH573-671 chemistry.chemical_classification Cisplatin Reactive oxygen species Kelch-Like ECH-Associated Protein 1 lcsh:Cytology Interleukin-6 Squamous Cell Carcinoma of Head and Neck Oral cancer SOXB1 Transcription Factors RNA-Binding Proteins Epithelial cell adhesion molecule Cell Biology respiratory system medicine.disease Epithelial Cell Adhesion Molecule Head and neck squamous-cell carcinoma Gene Expression Regulation Neoplastic 030104 developmental biology chemistry Cell culture Drug Resistance Neoplasm Head and Neck Neoplasms 030220 oncology & carcinogenesis Cancer research Reactive Oxygen Species medicine.drug Signal Transduction |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 8, Pp 1-15 (2020) |
| ISSN: | 2041-4889 |
| Popis: | Overexpression of epithelial cell adhesion molecule (EpCAM) has been associated with chemotherapeutic resistance, leads to aggressive tumor behavior, and results in an adverse clinical outcome. The molecular mechanism by which EpCAM enrichment is linked to therapeutic resistance via Nrf2, a key regulator of antioxidant genes is unknown. We have investigated the link between EpCAM and the Nrf2 pathway in light of therapeutic resistance using head and neck squamous cell carcinoma (HNSCC) patient tumor samples and cell lines. We report that EpCAM was highly expressed in Nrf2-positive and HPV-negative HNSCC cells. In addition, cisplatin-resistant tumor cells consisted of a higher proportion of EpCAMhigh cells compared to the cisplatin sensitive counterpart. EpCAMhigh populations exhibited resistance to cisplatin, a higher efficiency in colony formation, sphere growth and invasion capacity, and demonstrated reduced reactive oxygen species (ROS) activity. Furthermore, Nrf2 expression was significantly higher in EpCAMhigh populations. Mechanistically, expression of Nrf2 and its target genes were most prominently observed in EpCAMhigh populations. Silencing of EpCAM expression resulted in the attenuation of expressions of Nrf2 and SOD1 concomitant with a reduction of Sox2 expression. On the other hand, silencing of Nrf2 expression rendered EpCAMhigh populations sensitive to cisplatin treatment accompanied by the inhibition of colony formation, sphere formation, and invasion efficiency and increased ROS activity. The molecular mechanistic link between EpCAM expression and activation of Nrf2 was found to be a concerted interaction of interleukin-6 (IL-6) and p62. Silencing of p62 expression in EpCAMhigh populations resulted in the attenuation of Nrf2 pathway activation suggesting that Nrf2 pathway activation promoted resistance to cisplatin in EpCAMhigh populations. We propose that therapeutic targeting the Nrf2-EpCAM axis might be an excellent approach to modulate stress resistance and thereby survival of HNSCC patients enriched in EpCAMhigh populations. |
| Databáze: | OpenAIRE |
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