Vitamin K3 derivative inhibits androgen receptor signaling in targeting aggressive prostate cancer cells.

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY BioFactors Pub Date : 2024-09-03 DOI:10.1002/biof.2117
Somaiah Chinnapaka, Velavan Bakthavachalam, Subramanyam Dasari, Jhishnuraj Kannan, Sworaj Sapkota, Raj Kumar, Gnanasekar Munirathinam
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Abstract

Prostate cancer (PCa) is the second critical cause of cancer-related deaths, with African Americans dying at higher rates in the U.S. The main reasons for the higher mortality rate are ethnic differences and lack of understanding of prostate cancer biology and affordable treatments, as well as the financial burden of African American men to obtain the most effective and safe treatments. The effect of micronutrients, including Vitamin K, on various cancer cell lines has been widely studied, but the potential anticancer effect of VK3-OCH3, an analog of vitamin K3 (Menadione), on African American prostate cancer has not been evaluated. In this study, we compared the anticancer effect of VK3-OCH3 on targeting African American derived PCa cell lines namely RC77-T and MDA-PCa-2b. Our results show that VK3-OCH3 significantly inhibits the proliferation of both RC77-T and MDA-PCa-2b African American PCa cells and promotes apoptosis, and the underlying mechanism of cell death appears to be similar in both the cell lines. Notably, VK3-OCH3 inhibits colony-forming ability and induces apoptosis by blocking the cell cycle at G0 in African American PCa cells. VK3-OCH3 also acts as an anti-metastatic agent by inhibiting the migration ability of the metastatic properties of African American PCa cells. The cell death of African American PCa cells mediated by VK3-OCH3 is associated with the production of free radicals, such as intracellular and mitochondrial reactive oxygen species (ROS). Interestingly, antioxidants such as N-Acetylcysteine (NAC) and Glutathione (GSH) effectively negated the oxidative stress induced by VK3-OCH3 on PCa cell lines derived from African American patients. Of note, VK3-OCH3 reduces androgen receptor and prostate-specific antigen expression in these PCa cells. Furthermore, molecular dynamic studies reiterated that VK3-OCH3 strongly binds to the androgen receptor, suggesting that the androgen receptor is the potential molecular target of VK3-OCH3. In addition, Western blot analysis showed that VK3-OCH3 reduces the expression of androgen receptor, TRX2, and anti-apoptotic signaling molecules such as Bcl-2 and TCTP in the MDA-PCa-2b metastatic PCa cellular model. In conclusion, our results suggested that VK3-OCH3 is a promising anticancer agent that could potentially reduce the mortality rates of African American PCa patients, warranting further preclinical and translational studies.

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维生素 K3 衍生物可抑制针对侵袭性前列腺癌细胞的雄激素受体信号传导。
前列腺癌(PCa)是癌症相关死亡的第二大重要原因,在美国,非裔美国人的死亡率较高。造成死亡率较高的主要原因是种族差异、缺乏对前列腺癌生物学和可负担得起的治疗方法的了解,以及非裔美国男性为获得最有效、最安全的治疗方法而承担的经济负担。包括维生素 K 在内的微量营养素对各种癌细胞株的影响已被广泛研究,但维生素 K3 的类似物 VK3-OCH3(甲萘醌)对非裔美国人前列腺癌的潜在抗癌作用尚未进行评估。在这项研究中,我们比较了 VK3-OCH3 对非裔美国人衍生 PCa 细胞系(即 RC77-T 和 MDA-PCa-2b)的抗癌效果。结果表明,VK3-OCH3 能明显抑制 RC77-T 和 MDA-PCa-2b 非裔美国人 PCa 细胞的增殖,并促进细胞凋亡。值得注意的是,VK3-OCH3 可抑制非裔美国人 PCa 细胞的集落形成能力,并通过阻断 G0 细胞周期诱导细胞凋亡。VK3-OCH3 还能抑制非裔美国人 PCa 细胞的迁移能力,从而起到抗转移的作用。VK3-OCH3 介导的非裔美国人 PCa 细胞死亡与自由基的产生有关,如细胞内和线粒体活性氧(ROS)。有趣的是,N-乙酰半胱氨酸(NAC)和谷胱甘肽(GSH)等抗氧化剂能有效抑制 VK3-OCH3 对非裔美国人 PCa 细胞系诱导的氧化应激。值得注意的是,VK3-OCH3 降低了这些 PCa 细胞中雄激素受体和前列腺特异性抗原的表达。此外,分子动态研究再次表明,VK3-OCH3 能与雄激素受体紧密结合,这表明雄激素受体是 VK3-OCH3 的潜在分子靶标。此外,Western 印迹分析表明,在 MDA-PCa-2b 转移性 PCa 细胞模型中,VK3-OCH3 可降低雄激素受体、TRX2 以及 Bcl-2 和 TCTP 等抗凋亡信号分子的表达。总之,我们的研究结果表明,VK3-OCH3是一种很有前景的抗癌药物,有可能降低非裔美国人PCa患者的死亡率,值得进一步开展临床前和转化研究。
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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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