Department of Urology, Ji'nan Central Hospital, Ji'nan City, Shandong Province 250013, China.
Department of Urology, Ji'nan Central Hospital, Ji'nan City, Shandong Province 250013, China.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):697-703. doi: 10.1016/j.bbrc.2014.06.039. Epub 2014 Jun 16.
The prostate cancer is one of the leading causes of men's cancer mortality. The development of alternative chemotherapeutic strategies is urgent. Berberine has displayed significant anti-prostate cancer activities. The underlying mechanisms are not fully understood. In the current study, we found that berberine induced apoptosis and programmed necrosis in cultured prostate cancer cells (LNCaP and PC-82 lines), and necrosis weighted more than apoptosis in contributing berberine's cytotoxicity. We demonstrated that mitochondrial protein cyclophilin-D (Cyp-D) is required for berberine-induced programmed necrosis. Inhibition of Cyp-D by its inhibitors cyclosporin A (CSA) or sanglifehrin A (SFA), and by Cyp-D shRNA depletion alleviated berberine-induced prostate cancer cell necrosis (but not apoptosis). Our data found that in prostate cancer cells, berberine induced reactive oxygen species (ROS) production, which dictated P53 translocation to mitochondria, where it physically interacted with Cyp-D to open mitochondrial permeability transition pore (mPTP). The anti-oxidant N-acetylcysteine (NAC), the P53 inhibitor pifithrin-α (PFTα) as well as P53 siRNA knockdown suppressed berberine-induced P53 mitochondrial translocation and Cyp-D association, thus inhibiting mitochondrial membrane potential (MMP) decrease and prostate cancer cell necrosis. In summary, the results of the present study provide mechanistic evidence that both apoptosis and programmed necrosis attribute to berberine's cytotoxicity in prostate cancer cells.
前列腺癌是男性癌症死亡的主要原因之一。开发替代化疗策略迫在眉睫。小檗碱显示出显著的抗前列腺癌活性。其潜在机制尚未完全了解。在本研究中，我们发现小檗碱诱导培养的前列腺癌细胞（LNCaP 和 PC-82 系）凋亡和程序性坏死，程序性坏死在小檗碱的细胞毒性中比凋亡更为重要。我们证明线粒体蛋白亲环素-D（Cyp-D）是小檗碱诱导程序性坏死所必需的。其抑制剂环孢素 A（CSA）或桑福海林 A（SFA）或 Cyp-D shRNA 耗尽抑制 Cyp-D，可减轻小檗碱诱导的前列腺癌细胞坏死（但不诱导凋亡）。我们的数据发现，在前列腺癌细胞中，小檗碱诱导活性氧（ROS）的产生，从而促使 P53 易位到线粒体，在那里它与 Cyp-D 物理相互作用以打开线粒体通透性转换孔（mPTP）。抗氧化剂 N-乙酰半胱氨酸（NAC）、P53 抑制剂 pifithrin-α（PFTα）以及 P53 siRNA 敲低抑制了小檗碱诱导的 P53 线粒体易位和 Cyp-D 结合，从而抑制线粒体膜电位（MMP）下降和前列腺癌细胞坏死。总之，本研究结果提供了机制证据，表明凋亡和程序性坏死都导致了小檗碱对前列腺癌细胞的细胞毒性。
