Cyclin-dependent kinase inhibitors, roscovitine and purvalanol, induce apoptosis and autophagy related to unfolded protein response in HeLa cervical cancer cells

Abstract

Roscovitine (Rosc) and purvalanol (Pur) are competitive inhibitors of cyclin-dependent kinases (CDKs) by targeting their ATP-binding pockets. Both drugs are shown to be effective to decrease cell viability and dysregulate the ratio of pro- and anti-apoptotic Bcl-2 family members, which finally led to apoptotic cell death in different cancer cell lines in vitro. It was well established that Bcl-2 family members have distinct roles in the regulation of other cellular processes such as endoplasmic reticulum (ER) stress. The induction of ER stress has been shown to play critical role in cell death/survival decision via autophagy or apoptosis. In this study, our aim was to investigate the molecular targets of CDK inhibitors on ER stress mechanism related to distinct cell death types in time-dependent manner in HeLa cervical cancer cells. Our results showed that Rosc and Pur decreased the cell viability, cell growth and colony formation, induced ER stress-mediated autophagy or apoptosis in time-dependent manner. Thus, we conclude that exposure of cells to CDK inhibitors induces unfolded protein response and ER stress leading to autophagy and apoptosis processes in HeLa cervical cancer cells.

Purvalanol A induces apoptosis and reverses cisplatin resistance in ovarian cancer

“…In addition, growing evidence has shown that elevated ROS could regulate the AKT/mTOR signaling pathway [56,57]. A previous investigation has illustrated that Pur can selectively induce apoptosis in cancer cells by increasing intracellular ROS levels [51].…”

“…Besides, it has been suggested that autophagy and apoptosis signaling pathways can interact with each other [ 49 , 50 ]. Recent research declared that both autophagy and apoptosis could be enhanced by Pur in colon cancer [ 20 ] and cervical cancer cells [ 51 ]. Therefore, clarifying the role of autophagy, and understanding the interaction between apoptosis and autophagy may be conducive to explaining the underlying synergistic mechanism of Pur in EOC.…”

“…In addition, growing evidence has shown that elevated ROS could regulate the AKT/mTOR signaling pathway [ 56 , 57 ]. A previous investigation has illustrated that Pur can selectively induce apoptosis in cancer cells by increasing intracellular ROS levels [ 51 ]. In a study on prostate cancer, Pur increased apoptosis and autophagy in prostate cancer cells by suppressing PI3K/Akt/mTOR pathway [ 58 ].…”

Future Aspects of CDK5 in Prostate Cancer: From Pathogenesis to Therapeutic Implications

“…Therefore, it can be considered as a potential drug for treating cancers [79]. Roscovitine triggers apoptosis of cancer cells by increasing the expression level of p53 while decreasing anti-apoptotic proteins [80,81,82]. We also found a significant decrease in the growth of LNCaP prostate cancer cells as well as in a tumor xenograft animal model after Roscovitine treatment [83].…”

The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification

“…Category 1 hits included GW416981X, a potent CDK1-3 inhibitor. The CDK inhibitors roscovitine and purvalanol have previously been shown to induce autophagy [36]. Likewise, CHK1 inhibition, represented by the category 1 hit CCT244747, has been previously linked to autophagy induction [37].…”