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

IF 3.4 3区医学 Q1 DERMATOLOGY

Experimental Dermatology Pub Date : 2026-09-18 DOI:10.1111/exd.70344

Po-Hsuan Lu, Ling-Ya Chiu, Jen-Yu Wang, Pa-Fan Hsiao, Ping-Hsun Lu, Yi-Ting Huang, Yi-Ting Cheng, Nan-Lin Wu

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引用次数: 0

Abstract

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.

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Syk抑制使皮肤鳞状癌细胞对trail诱导的细胞凋亡敏感

脾酪氨酸激酶（Syk）调节免疫反应，并与造血和上皮癌有关。虽然我们之前的研究表明Syk调节角化细胞分化和uvb诱导的炎症，但其在uvb相关的皮肤鳞状细胞癌（cSCC）中的作用尚不清楚。肿瘤坏死因子相关凋亡诱导配体（TRAIL）选择性诱导癌细胞凋亡，在健康皮肤中表达，但在非黑色素瘤皮肤癌和日晒皮肤中表达减少。本研究探讨Syk在cSCC和trail诱导的细胞凋亡中的作用。免疫组织化学显示，与正常皮肤相比，SCC组织中磷酸化和总Syk水平升高。在SCC12细胞中，TRAIL诱导了剂量依赖性的细胞凋亡，而Syk抑制或Syk沉默可增强这种凋亡。TRAIL和Syk抑制剂联合治疗增加了annexin V的阳性和caspase-3、PARP1和Bid的裂解，同时降低了Mcl-1的表达。在机制上，TRAIL诱导Src和Syk磷酸化。trail诱导的Syk活化受Src抑制而不受EGFR抑制，表明在该途径中Syk活化依赖Src而不依赖EGFR。Syk抑制进一步降低trail激活的Akt和MAPK信号，而Akt激活可能在调节SCC12存活中发挥作用。这些结果表明，靶向Syk使trail介导的细胞凋亡增敏，可能为治疗皮肤鳞状细胞癌提供一种有希望的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental Dermatology 医学-皮肤病学

CiteScore

6.70

自引率

5.60%

发文量

201

审稿时长

2 months

期刊介绍： Experimental Dermatology provides a vehicle for the rapid publication of innovative and definitive reports, letters to the editor and review articles covering all aspects of experimental dermatology. Preference is given to papers of immediate importance to other investigators, either by virtue of their new methodology, experimental data or new ideas. The essential criteria for publication are clarity, experimental soundness and novelty. Letters to the editor related to published reports may also be accepted, provided that they are short and scientifically relevant to the reports mentioned, in order to provide a continuing forum for discussion. Review articles represent a state-of-the-art overview and are invited by the editors.