Hafeez Samra, Urooj Mahwish, Saleem Shamiala, Gillani Zeeshan, Shaheen Sumaira, Qazi Mahmood Husain, Naseer Muhammad Imran, Iqbal Zafar, Ansari Shakeel Ahmed, Haque Absarul, Asif Muhammad, Mir Manzoor Ahmad, Ali Ashraf, Pushparaj Peter Natesan, Jamal Mohammad Sarwar, Rasool Mahmood
Institute of Molecular Biology and Biotechnology and Center for Research in Molecular Medicine, the University of Lahore, Lahore, Pakistan.
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
PLoS One. 2016 Jan 8;11(1):e0145780. doi: 10.1371/journal.pone.0145780. eCollection 2016.
This study has been undertaken to explore the therapeutic effects of deguelin and specific siRNAs in HeLa cells. The data provided clearly show the silencing of ERK 1/2 with siRNAs and inhibition of ERK1/2 with deguelin treatment in HeLa cells. Additionally, we are providing information that deguelin binds directly to anti-apoptotic Bcl-2, Bcl-xl and Mcl-1 in the hydrophobic grooves, thereby releasing BAD and BAX from dimerization with these proteins. This results in increased apoptotic activity through the intrinsic pathway involved in rupture of mitochondrial membrane and release of cytochrome C. Evidence for inhibition of ERK1/2 by deguelin and escape of BAD phosphorylation at serine 112 through ERK/RSK pathway has been further fortified by obtaining similar results by silencing ERK 1/2 each with specific siRNAs. Increase in BAD after treatment with deguelin or siRNAs has been interpreted to mean that deguelin acts through several alternative pathways and therefore can be used as effective therapeutic agent.
本研究旨在探索鱼藤素和特定小干扰RNA（siRNA）对人宫颈癌细胞（HeLa细胞）的治疗效果。所提供的数据清楚地表明，在HeLa细胞中，siRNA可使细胞外信号调节激酶1/2（ERK 1/2）沉默，鱼藤素处理可抑制ERK1/2。此外，我们还提供了相关信息，即鱼藤素在疏水凹槽中直接与抗凋亡蛋白Bcl-2、Bcl-xl和Mcl-1结合，从而使BAD和BAX从与这些蛋白的二聚体中释放出来。这通过涉及线粒体膜破裂和细胞色素C释放的内在途径导致凋亡活性增加。通过用特定siRNA使ERK 1/2沉默获得类似结果，进一步证实了鱼藤素对ERK1/2的抑制作用以及BAD在丝氨酸112处通过ERK/核糖体S6激酶（RSK）途径的磷酸化逃逸。用鱼藤素或siRNA处理后BAD增加，这被解释为鱼藤素通过多种替代途径发挥作用，因此可作为有效的治疗药物。
