Syk Inhibition Sensitizes Skin Squamous Carcinoma Cells to TRAIL ‐Induced Apoptosis

Spleen tyrosine kinase (Syk) regulates immune responses and has been implicated in haematopoietic and epithelial cancers. Although our previous studies showed that Syk modulates keratinocyte differentiation and UVB-induced inflammation, its role in UVB-related cutaneous squamous cell carcinoma (cSCC) remains unclear. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells and is expressed in healthy skin but reduced in non-melanoma skin cancers and sun-exposed skin. This study investigated the role of Syk in cSCC and TRAIL-induced apoptosis. Immunohistochemistry revealed elevated phosphorylated and total Syk levels in SCC tissues compared with normal skin. In SCC12 cells, TRAIL induced dose-dependent apoptosis, which was enhanced by pharmacological Syk inhibition or Syk silencing. Combination treatment with TRAIL and Syk inhibitors increased annexin V positivity and cleavage of caspase-3, PARP1 and Bid, accompanied by reduced Mcl-1 expression. Mechanistically, TRAIL induced Src and Syk phosphorylation. TRAIL-induced Syk activation was suppressed by Src inhibition but not by EGFR inhibition, indicating that Syk activation is Src-dependent but EGFR-independent in this pathway. Syk inhibition further reduced TRAIL-activated Akt and MAPK signalling, while Akt activation may play a role in regulating SCC12 survival. These results suggest that targeting Syk sensitizes TRAIL-mediated apoptosis and may offer a promising therapeutic strategy for treating cutaneous SCC.