Imiquimod induces apoptosis of squamous cell carcinoma (SCC) cells via regulation of A20.

Kyung-Cheol Sohn,Tiejun Zhang,Dae-Kyoung Choi,Jae Woo Lim,Zheng Jun Li,Myung Im,Chang Deok Kim,Gang Min Hur,Young Lee,In-Kyu Chang,Young-Joon Seo,Jeung-Hoon Lee,Hiroyasu Nakano

doi:10.1371/journal.pone.0095337

Kyung-Cheol Sohn, Tiejun Zhang + Show 11 more

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https://doi.org/10.1371/journal.pone.0095337

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Journal: PloS one	Publication Date: Apr 17, 2014
Citations: 31	License type: CC BY 4.0

Affiliation: Chungnam National University

Abstract

Imiquimod, a nucleoside analogue of the imidazoquinoline family, is being used to treat various cutaneous cancers including squamous cell carcinoma (SCC). Imiquimod activates anti-tumor immunity via Toll-like receptor 7 (TLR7) in macrophage and other immune cells. Imiquimod can also affect tumor cells directly, regardless of its impact on immune system. In this study, we demonstrated that imiquimod induced apoptosis of SCC cells (SCC12) and A20 was involved in this process. When A20 was overexpressed, imiquimod-induced apoptosis was markedly inhibited. Conversely, knockdown of A20 potentiated imiquimod-induced apoptosis. Interestingly, A20 counteracted activation of c-Jun N-terminal kinase (JNK), suggesting that A20-regulated JNK activity was possible mechanism underlying imiquimod-induced apoptosis of SCC12 cells. Finally, imiquimod-induced apoptosis of SCC12 cells was taken place in a TLR7-independent manner. Our data provide new insight into the mechanism underlying imiquimod effect in cutaneous cancer treatment.

Highlights

Squamous cell carcinoma (SCC) is one of epithelial cancers, which is originated from the upper layers of skin epidermis
We demonstrated that imiquimod induced apoptosis of SCC cells and antiapoptotic regulator A20 was involved in this process
We showed that imiquimod treatment led to down-regulation of A20 in SCC12 cells

Summary

Introduction

Squamous cell carcinoma (SCC) is one of epithelial cancers, which is originated from the upper layers of skin epidermis. Ultraviolet (UV) radiation is the best-known cause of SCC, which primarily affects DNA thereby inducing mutations of many susceptible genes including p53 [2]. Intracellular signal regulators such as epidermal growth factor receptor (EGFR), Src-family tyrosine kinase Fyn, and nuclear factor k-light-chain-enhancer of activated B cells (NF-kB) are implicated in the development of SCC [3,4,5,6]. Imiquimod as a 5% cream is used to treat several skin diseases, including malignant melanoma, basal cell carcinoma (BCC), and SCC [9,10,11]. We hypothesize that imiquimod has direct effect on SCC cells, regardless of its impact on immune system

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