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 (eIF2α)/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/eIF2α/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/eIF2α/ATF4/CHOP pathway and inhibiting the AKT/mTOR pathway. Thus, our study shows that CCT020312 may be a potential drug candidate for TNBC treatment.
Highlights
Breast cancer is one of the most common cancers in women, and triple-negative breast cancer (TNBC) is the most aggressive breast cancer, resulting in a poor outcome because of high molecular heterogeneity and metastatic potential, and a lack of therapeutic targets (Chang-Qing et al, 2019)
The detailed information of primary antibodies against cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved poly (ADP-ribose) polymerase (PARP), protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated PERK (p-PERK), eukaryotic translation initiation factor 2 alpha (eIF2a), p-eIF2a, activating transcription factor 4 (ATF4), CHOP, protein kinase B (AKT), pAKT, mammalian target of rapamycin, p-mTOR, and Ki-67 is presented in Supplementary Table S1
To the best of our knowledge, this is the first study to show that CCT020312, a selective activator of eIF2a/PERK, exerts its antiTNBC effects by inducing G1 phase arrest and apoptosis via the activation of the PERK/eIF2a/ATF4/CHOP pathway and inactivation of the AKT/mTOR pathway
Summary
Breast cancer is one of the most common cancers in women, and triple-negative breast cancer (TNBC) is the most aggressive breast cancer, resulting in a poor outcome because of high molecular heterogeneity and metastatic potential, and a lack of therapeutic targets (Chang-Qing et al, 2019). Due to the absence of these receptors, TNBC does not respond to endocrine therapies, such as tamoxifen, and to HER2-targeting therapies such as herceptin (Jiang et al, 2019). Traditional firstline drugs for treating breast cancer, such as paclitaxel, are not very effective against TNBC. Second-line drugs that are used to treat breast cancer, such as cisplatin, appear to be more effective against TNBC. Patients with TNBC have a poor prognosis compared with patients with other types of breast cancer (Zhao et al, 2019)
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