CCT020312 Inhibits Triple-Negative Breast Cancer Through PERK Pathway-Mediated G1 Phase Cell Cycle Arrest and Apoptosis

Abstract

Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific therapeutic targets. CCT020312, a selective eukaryotic translation initiation factor 2 alpha (eIF2a)/protein kinase RNA-like endoplasmic reticulum kinase (PERK) activator, may have a potent anti-tumor effect. In the present study, we examined the effects of CCT020312 on TNBC and explored the underlying mechanism. We found that CCT020312 inhibited the viability of TNBC cell lines, MDA-MB-453 and CAL-148, by inducing apoptosis and G1 phase cell cycle arrest. CCT020312 decreased the protein levels of cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, and B-cell lymphoma 2 (Bcl-2) and increased the levels of Bcl-2-associated X protein (Bax) and cleaved poly (ADP-ribose) polymerase (PARP) compared with those in the control. CCT020312 activated PERK/eIF2a/activating transcription factor 4 (ATF4)/CCAAT-enhancer binding protein (C/EBP) homologous protein transcription factor (CHOP) signaling and inhibited protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling. Furthermore, CCT020312 inhibited tumor growth in an MDA-MB-453 orthotopic xenograft mouse model by activating the PERK/eIF2a/ATF4/CHOP pathway and inhibiting the AKT/mTOR pathway. Thus, our study shows that CCT020312 may be a potential drug candidate for TNBC treatment.

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

“…The compound CCT020312 was found in a phenotypic screen that assayed for G1/S checkpoint activators in human colon carcinoma cells [190]. It also inhibited triple-negative breast cancer by G1 phase cell cycle arrest [191]. CCT020312 showed neuroprotection in cellular and mouse models of tauopathies, reducing tau phosphorylation in P301S tau mice and significantly improving their memory and motor function, with a reduction in motoneuron loss [129].…”

Differential Regulation of Lacto-/Neolacto- Glycosphingolipid Biosynthesis Pathway Reveals Transcription Factors as Potential Candidates in Triple-Negative Breast Cancer

“…The top 10 significant KEGG pathways derived from GSEA among the three datasets showed only two common pathways, cell cycle and glycosphingolipid biosynthesis lacto/neolacto series (Figure 4C). Discovery of the cell cycle pathway validates our approach as cell cycle deregulation is known in TNBC, and cell cycle-targeting drugs have shown promise in clinical trials [35]. Focusing on glycosylation pathways that were enriched in all three datasets, regardless of ranking, we identified three more pathways: glycosylphosphatidylinositol (GPI)-anchor biosynthesis, which was down-regulated in TNBC, and two pathways in glycosaminoglycan biosynthesis which were up-regulated in TNBC (Figure 4D).…”

Giardia duodenalis-induced G0/G1 intestinal epithelial cell cycle arrest and apoptosis involve activation of endoplasmic reticulum stress in vitro

“…Some studies have reported that the activation of ER stress signaling pathway IRE1-XBP1s induces cell cycle arrest by increasing expressions of p21 and p27 ( 7 ). The activation of PERK/eIF2α signaling has been shown to cause loss of cyclin D1, resulting in G1 cell cycle arrest ( 6 , 47 ). However, the current study does not demonstrate a direct association of activation of ATF6 signaling pathway with cell cycle progression.…”