Copanlisib promotes growth inhibition and apoptosis by modulating the AKT/FoxO3a/PUMA axis in colorectal cancer

Abstract

Colorectal cancer (CRC) is the type of cancer with the third highest incidence and is associated with high mortality and low 5-year survival rates. We observed that copanlisib, an inhibitor of PI3K (pan-class I phosphoinositide 3-kinase) that preferentially inhibits PI3Kδ and PI3Kα, impedes the growth of CRC cells by inducing apoptosis via PUMA. There was a marked increase in the expression of PUMA independent of p53 after treatment with copanlisib. The response of CRC cells to copanlisib could be predicted by PUMA expression. Copanlisib was found to induce PUMA expression through FoxO3a by directly binding to the PUMA promoter after inhibiting AKT signaling. PUMA deficiency mitigated the apoptosis induced by copanlisib. Caspase activation and mitochondrial dysfunction led to copanlisib resistance, as observed through a clonogenic assay, whereas enhanced expression of PUMA increased the copanlisib-induced susceptibility to apoptosis. Moreover, the antitumor effects of copanlisib were suppressed by a deficiency of PUMA in a xenograft model, and caspase activation and reduced apoptosis were also observed in vivo. Copanlisib-mediated chemosensitization seemed to involve the concurrent induction of PUMA expression via mechanisms that were both dependent and independent of p53. These observations indicate that apoptosis mediated by PUMA is crucial for the anticancer effects of copanlisib and that manipulation of PUMA may aid in enhancing anticancer activities.

Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors

“…In the present study, PI3K inhibitors upregulated proapoptotic BCL family members including PUMA and BIM both at the mRNA and protein levels, whereas neither of the anti-apoptotic BCL family members including BCL-2, BCL-XL and MCL-1 were not downregulated in TRS-derived cell lines such as SS, ES and ARMS. The upregulation of FOXO1 and/or FOXO3 in cells undergoing apoptosis after blockade of the PI3K pathway suggested the involvement of FOXO1/3 in the induction of PUMA and BIM, as previously reported in cell lines derived from hepatocellular carcinoma and colorectal cancers [ 30 , 31 ]. FOXO transcription factors are known to be downstream factors of the PI3K/Akt signaling pathway and their expression can be degraded by the ubiquitin-proteasome pathway via phosphorylation by Akt [ 46 ].…”

“…Induction of FOXO1/3, but not p53, in TRS cell lines undergoing apoptosis triggered by PI3K blockade It was previously reported that PI3K inhibition induces apoptosis by upregulating forkhead box O1/3 (FOXO1/3), transcription factors downstream of PI3K signaling, and thereby transactivate the expression of PUMA or BIM in hepatocellular carcinoma and colorectal cancer, respectively [30,31]. Other studies demonstrated that apoptotic stimuli by DNA damaging agents activate p53, leading to apoptosis via the transcriptional upregulation of PUMA, NOXA, BID and BAX [32][33][34][35].…”

Ribosomal L1 domain-containing protein 1 coordinates with HDM2 to negatively regulate p53 in human colorectal Cancer cells

“…1 D and E). To investigate how RSL1D1 regulates PUMA expression in HCT116 p53−/− cells, we determined the protein level of FOXO3a, a direct transcriptional regulator of PUMA that mainly contributes to the p53-independent upregulation of PUMA in CRC cells [ 42 , 43 ]. Upon RSL1D1 knockdown, the level of FOXO3a protein increased in HCT116 p53−/− other than HCT116 p53+/+ cells (Supplementary Fig.…”

Recent advances of bioactive proteins/polypeptides in the treatment of breast cancer

“…Cancer cells are capable of evading apoptosis (Brown and Attardi, 2005 ). Reactive oxygen species (ROS) increase the levels of phosphatase and tensin homolog (PTEN), as a tumor suppressor gene, negatively regulating PI3K/Akt pathway (Wang et al, 2020 , 2022 ), thereby inducing caspases-dependent apoptosis through itself, forkhead box O3a (FoxO3a) (Yan et al, 2020 ), and glycogen synthase kinase 3-β (GSK3β) (Guo et al, 2020 ). Members of the caspase family participate in the initiation and execution of apoptosis (Boice and Bouchier-Hayes, 2020 ).…”