Upregulation of GCLC is Responsible for SFN‐induced Tumor Cell Proliferation

GCLC公司 小发夹RNA 细胞生长 GCLM公司 下调和上调 化学 基因敲除 谷胱甘肽 癌症研究 莱菔硫烷 分子生物学 细胞凋亡 生物 生物化学 基因
作者
Chan Ho Jang,Jinkyung Lee,Min Jeong Kwon,Yoonsu Kim,Ji Hyeong Chae,Yoon Ah Jeong,Eun Jeong Kwon,Jisun Oh,Jong‐Sang Kim
出处
期刊:The FASEB Journal [Wiley]
卷期号:36 (S1)
标识
DOI:10.1096/fasebj.2022.36.s1.r4214
摘要

Sulforaphane (SFN), a sulfur-containing compound that belongs to the isothiocyanate class of dietary phytochemicals found in cruciferous vegetables, has been known to cause a hormetic effect on cancer cell growth. We previously reported that SFN at low doses stimulated proliferation of HCT116 human colorectal carcinoma cells through Nrf2 activation in vitro and in vivo. Recently, we discovered that brusatol, a nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, significantly suppressed the SFN-induced proliferation of HCT116 cells. Therefore, we hypothesized that SFN-induced proliferation of HCT116 cells is mediated by an Nrf2 downstream gene(s). Transcriptomic profiling revealed a set of differentially expressed genes (DEGs) involved in glutathione (GSH) metabolism as compared between wildtype (WT) and Nrf2 knockout (KO) HCT116 cells treated with or without SFN. In particular, we found that glutamate-cysteine ligase catalytic subunit (GCLC) was highly elevated in SFN-treated WT HCT116 cells among the DEGs, but not in SFN-treated Nrf2 KO HCT116 cells. To confirm if upregulation of γ-glutamate-cysteine ligase (γ-GCL) is associated with SFN-induced proliferation of HCT116 cells, inhibiting γ-GCL by buthionine sulfoximine (BSO, a selective γ-GCL inhibitor) and silencing GCLC by short hairpin RNA (shRNA) were carried out. The results showed that SFN-induced proliferation of HCT116 cells was significantly reduced by γ-GCL inhibition and abolished by GCLC knockdown. Furthermore, we confirmed that BSO suppressed SFN-induced tumor growth of WT HCT116 xenograft mice and the tumor growth was not stimulated in both Nrf2 KO and GCLC shRNA HCT16 xenograft mice by SFN at a low dose. Collectively, these findings indicate that upregulation of GCLC-dependent GSH biosynthesis by SFN promotes proliferation of HCT116 cells and thus GCL could be a potential target for chemotherapy.

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