Int J Oral Biol.  2021 Dec;46(4):176-183. 10.11620/IJOB.2021.46.4.176.

Characterization of intracellular Ca²⁺ mobilization in gefitinib-resistant oral squamous carcinoma cells HSC-3 and -4

• Kim MS
• Kim MS

• KMID: 2524299
• DOI: http://doi.org/10.11620/IJOB.2021.46.4.176

Abstract

Oral squamous cell carcinoma (OSCC) metastasis is characterized by distant metastasis and local recurrence. Combined chemotherapy with cisplatin and 5-fluorouracil is routinely used to treat patients with OSCC, and the combined use of gefitinib with cytotoxic drugs has been reported to enhance the sensitivity of cancer cells in vitro. However, the development of drug resistance because of prolonged chemotherapy is inevitable, leading to a poor prognosis. Therefore, understanding alterations in signaling pathways and gene expression is crucial for overcoming the development of drug resistance. However, the altered characterization of Ca²⁺ signaling in drug-resistant OSCC cells remains unclear. In this study, we investigated alterations in intracellular Ca²⁺ ([Ca²⁺ ]_i ) mobilization upon the development of gefitinib resistance in human tongue squamous carcinoma cell line (HSC)-3 and HSC-4 using ratiometric analysis. This study demonstrated the presence of altered epidermal growth factor- and purinergic agonist-mediated [Ca²⁺ ]_i mobilization in gefitinib-resistant OSCC cells. Moreover, Ca ²⁺ content in the endoplasmic reticulum, store-operated calcium entry, and lysosomal Ca²⁺ release through the transient receptor potential mucolipin 1, were confirmed to be significantly reduced upon the development of apoptosis resistance. Consistent with [Ca²⁺ ]_i mobilization, we identified modified expression levels of Ca²⁺ signaling-related genes in gefitinib-resistant cells. Taken together, we propose that the regulation of [Ca²⁺ ]_i mobilization and related gene expression can be a new strategy to overcome drug resistance in patients with cancer.

Keyword

Squamous cell carcinoma of head and neck; Gefitinib; Drug resistance; Calcium channel