Synergistic anti-tumour effect of syk inhibitor and olaparib in squamous cell carcinoma: Roles of syk in EGFR signalling and PARP1 activation
Journal
Cancers
Journal Volume
12
Journal Issue
2
Pages
489
Date Issued
2020
Author(s)
Abstract
Syk is a non-receptor tyrosine kinase involved in the signalling of immunoreceptors and growth factor receptors. Previously, we reported that Syk mediates epidermal growth factor receptor (EGFR) signalling and plays a negative role in the terminal differentiation of keratinocytes. To understand whether Syk is a potential therapeutic target of cancer cells, we further elucidated the role of Syk in disease progression of squamous cell carcinoma (SCC), which is highly associated with EGFR overactivation, and determined the combined effects of Syk and PARP1 inhibitors on SCC viability. We found that pharmacological inhibition of Syk could attenuate the EGF-induced phosphorylation of EGFR, JNK, p38 MAPK, STAT1, and STAT3 in A431, CAL27 and SAS cells. In addition, EGF could induce a Syk-dependent IL-8 gene and protein expression in SCC. Confocal microscopic data demonstrated the ability of the Syk inhibitor to change the subcellular distribution patterns of EGFR after EGF treatment in A431 and SAS cells. Moreover, according to Kaplan-Meier survival curve analysis, higher Syk expression is correlated with poorer patient survival rate and prognosis. Notably, both Syk and EGFR inhibitors could induce PARP activation, and synergistic cytotoxic actions were observed in SCC cells upon the combined treatment of the PARP1 inhibitor olaparib with Syk or the EGFR inhibitor. Collectively, we reported Syk as an important signalling molecule downstream of EGFR that plays crucial roles in SCC development. Combining Syk and PARP inhibition may represent an alternative therapeutic strategy for treating SCC. ? 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Subjects
EGFR; PARP; Squamous cell carcinoma; Syk
Other Subjects
epidermal growth factor receptor; mitogen activated protein kinase p38; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; olaparib; protein kinase Syk inhibitor; STAT1 protein; STAT3 protein; stress activated protein kinase; A-431 cell line; aged; antineoplastic activity; Article; CAL-27 cell line; cell viability; cellular distribution; clinical effectiveness; controlled study; cytotoxicity; drug effect; drug efficacy; drug mechanism; drug potentiation; drug response; enzyme activation; female; human; human cell; human tissue; major clinical study; male; protein expression; protein phosphorylation; SAS cell line; signal transduction; squamous cell carcinoma; survival rate
Type
journal article