结肠癌细胞中 3-巯基丙酮酸硫转移酶对 CyR61 表达和释放的调节,Redox Biology

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结肠癌细胞中 3-巯基丙酮酸硫转移酶对 CyR61 表达和释放的调节
Redox Biology ( IF 10.7 ) Pub Date : 2022-09-08 , DOI: 10.1016/j.redox.2022.102466
Kelly Ascenção ₁ , Bassma Lheimeur ₁ , Csaba Szabo ₁

Affiliation

富含半胱氨酸的血管生成诱导剂 61（CYR61，也称为 CCN 家族成员 1 或 CCN1）是由 CYR61 基因编码的基质细胞蛋白。该蛋白参与多种癌症相关过程的调节，包括肿瘤生长、血管生成、肿瘤细胞粘附、迁移和侵袭以及抗癌药物耐药性的调节。硫化氢 (HS) 是一种气态内源性生物介质，参与多种癌症的细胞生物能、血管生成、侵袭和化疗耐药的调节。 HS 由三种酶产生：胱硫醚-β-合酶 (CBS)、胱硫醚-γ-裂解酶 (CSE) 和 3-巯基丙酮酸硫转移酶 (3-MST)。目前的研究旨在调查 CBS 或 3-MST 是否在调节增殖、迁移和存活的背景下调节结肠癌细胞中的 CyR61。该研究主要利用 HCT116 细胞，其中两种主要的 HS 产生酶 CBS 和 3-MST 高度表达。 HS 供体 GYY4137 和多硫化物供体 NaS 以浓度依赖性方式激活 CyR61 启动子。氨基氧乙酸 (AOAA)，CBS 和 HMPSNE 的药理学抑制剂：2-[(4-羟基-6-甲基嘧啶-2-基)硫基]-1-(萘-1-基)乙烷-1-酮， 3-MST 的药理学抑制剂抑制 CyR61 mRNA 表达。这种效应对 HMPSNE 的反应比对 AOAA 的反应更明显，并且是通过 ATF1 和 CREB 调节 S1PR 来实现的。 CyR61被发现在维持结肠细胞增殖方面发挥着积极但相对较小的作用。 HMPSNE 显着抑制结肠癌细胞分泌/释放 CyR61。此外，HMPSNE促进结肠癌细胞凋亡；研究发现内源产生的 CyR61 可以抵消这种效应，至少部分是通过 RhoA 激活来抵消的。综上所述，我们得出结论，癌细胞中 3-MST 的上调可发挥细胞保护作用，并赋予癌细胞更具侵袭性的表型——至少部分是通过调节 CyR61 表达和释放来实现的。

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Regulation of CyR61 expression and release by 3-mercaptopyruvate sulfurtransferase in colon cancer cells

Cysteine-rich angiogenic inducer 61 (CYR61, also termed CCN family member 1 or CCN1), is a matricellular protein encoded by the CYR61 gene. This protein has been implicated in the regulation of various cancer-associated processes including tumor growth, angiogenesis, tumor cell adhesion, migration, and invasion as well as the regulation of anticancer drug resistance. Hydrogen sulfide (HS) is a gaseous endogenous biological mediator, involved in the regulation of cellular bioenergetics, angiogenesis, invasion, and chemotherapeutic resistance in several types of cancer. HS is produced by three enzymes: cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current studies were set up to investigate if CBS or 3-MST regulates CyR61 in colon cancer cells in the context of the regulation of proliferation, migration, and survival. The study mainly utilized HCT116 cells, in which two of the principal HS-producing enzymes, CBS and 3-MST, are highly expressed. The HS donor GYY4137 and the polysulfide donor NaS activated the CyR61 promoter in a concentration-dependent fashion. Aminooxyacetic acid (AOAA), a pharmacological inhibitor of CBS as well as HMPSNE: 2-[(4-hydroxy-6- methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one, a pharmacological inhibitor of 3-MST inhibited CyR61 mRNA expression. This effect was more pronounced in response to HMPSNE than to AOAA and occurred through the modulation of S1PR via ATF1 and CREB. CyR61 was found to play an active, but relatively minor role in maintaining colon cell proliferation. HMPSNE markedly suppressed the secretion/release of CyR61 from the colon cancer cells. Moreover, HMPSNE promoted colon cancer cell apoptosis; endogenously produced CyR61 was found to counteract this effect, at least in part via RhoA activation. Taken together, we conclude that the upregulation of 3-MST in cancer cells exerts cytoprotective effects and confers the cancer cells a more aggressive phenotype – at least in part via the modulation of CyR61 expression and release.

更新日期：2022-09-08

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