Chemotherapeutic resistance of head and neck squamous cell carcinoma is mediated by EpCAM induction driven by IL-6/p62 associated Nrf2-antioxidant pathway activation

Abu Shadat M Noman; Rashed R Parag; Muhammad I Rashid; Shafiqul Islam; Mohammad Z Rahman; Ali A Chowdhury; Afrin Sultana; Chandsultana Jerin; Ayesha Siddiqua; Lutfur Rahman; Junayed Nayeem; Sonam Akther; Sunanda Baidya; Rajib K Shil; Mizanur Rahman; Afsana Shirin; Reaz Mahmud; S M Ikram Hossain; Sharmin A Sumi; Arfina Chowdhury; Shabnam B Basher; Abul Hasan; Shammy Bithy; Jannatul Aklima; Nabila Chowdhury; Muhammad N Hasan; Tahmina Banu; Srikanta Chowdhury; Muhammad M Hossain; Herman Yeger; Walid A Farhat; Syed S Islam

doi:10.1038/s41419-020-02907-x

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Chemotherapeutic resistance of head and neck squamous cell carcinoma is mediated by EpCAM induction driven by IL-6/p62 associated Nrf2-antioxidant pathway activation

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Chemotherapeutic resistance of head and neck squamous cell carcinoma is mediated by EpCAM induction driven by IL-6/p62 associated Nrf2-antioxidant pathway activation

Abu Shadat M Noman, Rashed R Parag, Muhammad I Rashid, Shafiqul Islam, Mohammad Z Rahman, Ali A Chowdhury, Afrin Sultana, Chandsultana Jerin, Ayesha Siddiqua, Lutfur Rahman, …

Cell death & disease, Vol.11(8), pp.663-663

20/08/2020

DOI: https://doi.org/10.1038/s41419-020-02907-x

PMID: 32814771

Abstract

Antioxidants - pharmacology

Cell Line, Tumor

Cisplatin - pharmacology

Drug Resistance, Neoplasm - genetics

Drug Resistance, Neoplasm - physiology

Epithelial Cell Adhesion Molecule - metabolism

Epithelial Cell Adhesion Molecule - physiology

Gene Expression Regulation, Neoplastic - drug effects

Head and Neck Neoplasms - genetics

Head and Neck Neoplasms - metabolism

Humans

Interleukin-6 - metabolism

Kelch-Like ECH-Associated Protein 1 - metabolism

NF-E2-Related Factor 2 - metabolism

NF-E2-Related Factor 2 - physiology

Reactive Oxygen Species - metabolism

RNA-Binding Proteins - metabolism

Signal Transduction - drug effects

SOXB1 Transcription Factors

Squamous Cell Carcinoma of Head and Neck - genetics

Squamous Cell Carcinoma of Head and Neck - metabolism

Squamous Cell Carcinoma of Head and Neck - physiopathology

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 EpCAM cells compared to the cisplatin sensitive counterpart. EpCAM 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 EpCAM populations. Mechanistically, expression of Nrf2 and its target genes were most prominently observed in EpCAM 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 EpCAM 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 EpCAM populations resulted in the attenuation of Nrf2 pathway activation suggesting that Nrf2 pathway activation promoted resistance to cisplatin in EpCAM 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 EpCAM populations.

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Title: Chemotherapeutic resistance of head and neck squamous cell carcinoma is mediated by EpCAM induction driven by IL-6/p62 associated Nrf2-antioxidant pathway activation
Creators - without role: Abu Shadat M Noman - McGill University
Rashed R Parag - University of Chittagong
Muhammad I Rashid - University of Chittagong
Shafiqul Islam - University of Chittagong
Mohammad Z Rahman - Chittagong Medical College
Ali A Chowdhury - Chittagong Medical College
Afrin Sultana - University of Chittagong
Chandsultana Jerin - University of Chittagong
Ayesha Siddiqua - University of Chittagong
Lutfur Rahman - University of Chittagong
Junayed Nayeem - University of Chittagong
Sonam Akther - University of Chittagong
Sunanda Baidya - University of Chittagong
Rajib K Shil - University of Chittagong
Mizanur Rahman - Department of Biochemistry, Rangamati Medical College, Rangamati, Bangladesh
Afsana Shirin - University of Chittagong
Reaz Mahmud - University of Chittagong
S M Ikram Hossain - University of Chittagong
Sharmin A Sumi - University of Chittagong
Arfina Chowdhury - University of Chittagong
Shabnam B Basher - University of Chittagong
Abul Hasan - University of Chittagong
Shammy Bithy - University of Chittagong
Jannatul Aklima - University of Chittagong
Nabila Chowdhury - University of Chittagong
Muhammad N Hasan - University of Chittagong
Tahmina Banu - University of Chittagong
Srikanta Chowdhury - University of Chittagong
Muhammad M Hossain - University of Chittagong
Herman Yeger - Hospital for Sick Children
Walid A Farhat - University of Wisconsin American Family Children's Hospital
Syed S Islam - Alfaisal University
Publication Details: Cell death & disease, Vol.11(8), pp.663-663
Identifiers: 9913977208331
Academic Unit: King Faisal University; Alfaisal University
Language: English
Resource Type: Journal article