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.
Highlights
Colorectal cancer (CRC) is a frequently occurring and widely observed malignancy[1,2]
Copanlisib promotes growth inhibition and apoptosis in CRC cells To investigate the effect of copanlisib on CRC cells, we first examined the viability of the CRC cells treated for 72 h with increasing concentrations of copanlisib
The MTS results demonstrated that copanlisib inhibits CRC cell proliferation (Fig. 1A)
Summary
Colorectal cancer (CRC) is a frequently occurring and widely observed malignancy[1,2]. CRC is the third and second most common cancer in male and female patients, respectively, and its mortality rate is the fourth and third highest in these groups, respectively[3,4]. Copanlisib ( known as BAY 80-6946) is a pan-class I PI3K IV inhibitor with dominant activity toward PI3Kα and PI3Kδ10. Copanlisib has exhibited preclinical antitumor activity in diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL)[11]. The early demonstration of the clinical activity of copanlisib in FL and DLBCL was confirmed in phase 2 studies and extended to MZL, MCL, PTCL (peripheral T cell lymphoma), and small lymphocytic lymphoma[12]. Copanlisib is approved by the FDA for relapsed FL patients after at least
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