Characterization of intracellular Ca2+ mobilization in gefitinib-resistant oral squamous carcinoma cells HSC-3 and -4
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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, Ca2+ 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.
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, Ca2+ 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.
참고문헌 (24)
- Di Gennaro E, "Critical role of both p27KIP1 and p21CIP1", WAF1 in the antiproliferative effect of ZD1839 (‘Iressa’), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells, 2003, pp.195, 139~150
- Khalil A, "The EGFR inhibitor gefitinib enhanced the response of human oral squamous cell carcinoma to cisplatin in vitro", Drugs R D, 17, pp.545~555 (2017)[DOI]
- Cohen EE, "Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck", J Clin Oncol, 21, pp.1980~1987 (2003)[DOI]
- Zhang P, "Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line", BMC Cancer, 6, pp.224~ (2006)[DOI]
- Monteith GR, "Calcium channels and pumps in cancer : changes and consequences", J Biol Chem, 287, pp.31666~31673 (2012)[DOI]
- Frederick BA, "Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma", Mol Cancer Ther, 6, pp.1683~1691 (2007)[DOI]
- Cui C, "Targeting calcium signaling in cancer therapy", Acta Pharm Sin B, 7, pp.3~17 (2017)[DOI]
- Kondratska K, "Orai1 and STIM1mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma", Biochim Biophys Acta, 1843, pp.2263~2269 (2014)[DOI]
- VanHouten J, "PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer", Proc Natl Acad Sci U S A, 107, pp.11405~11410 (2010)[DOI]
- Li RF, "Overexpression of T-type calcium channel Cav3.1 in oral squamous cell carcinoma: association with proliferation and antiapoptotic activity", J Mol Histol, 52, pp.511~520 (2021)[DOI]
- Grandis JR, "Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer", Cancer Res, 53, pp.3579~3584 (1993)
- Berridge MJ, "The versatility and universality of calcium signalling", Nat Rev Mol Cell Biol, 1, pp.11~21 (2000)[DOI]
- Bugshan A, "Oral squamous cell carcinoma: metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis", F1000Res, 9, pp.229~ (2020)[DOI]
- Magné N, "Sequence-dependent effects of ZD1839(‘Iressa’)in combination with cytotoxic treatment in human head and neck cancer", Br J Cancer, 86, pp.819~827 (2002)[DOI]
- Rubin Grandis J, "Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival", J Natl Cancer Inst, 90, pp.824~832 (1998)[DOI]
- Bryant JA, "EGF activates intracellular and intercellular calcium signaling by distinct pathways in tumor cells", Cancer Biol Ther, 3, pp.1243~1249 (2004)[DOI]
- Di Virgilio F, "Extracellular purines, purinergic receptors and tumor growth", Oncogene, 36, pp.293~303 (2017)[DOI]
- Di Virgilio F, "Extracellular ATP and P2 purinergic signalling in the tumour microenvironment", Nat Rev Cancer, 18, pp.601~618 (2018)[DOI]
- Mantel A, "P2X7", PANX1 as a new target for melanoma, 2015, pp.24, 336~337
- Berridge MJ, "Calcium signalling:dynamics, homeostasis and remodelling", Nat Rev Mol Cell Biol, 4, pp.517~529 (2003)[DOI]
- Flourakis M, "Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells", Cell Death Dis, 1, pp.e75~ (2010)[DOI]
- Morgan AJ, "Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease", Biochem J, 439, pp.349~374 (2011)[DOI]
- Machado E, "Regulated lysosomal exocytosis mediates cancer progression", Sci Adv, 1, pp.e1500603~ (2015)[DOI]
- Jung J, "HRAS-driven cancer cells are vulnerable to TRPML1 inhibition", EMBO Rep, 20, pp.e46685~ (2019)[DOI]