Idelalisib induces PUMA-dependent apoptosis in colon cancer cells

Abstract

Idelalisib, a PI3K inhibitor, specifically targeting p110δ, has been approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. However, the mechanisms of action of idelalisib in colon cancer cells are not well understood. We investigated how idelalisib suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. In this study, we found that idelalisib treatment induces PUMA in colon cancer cells irrespective of p53 status through the p65 pathway following AKT inhibition and glycogen synthase kinase 3β (GSK3β) activation. PUMA is necessary for idelalisib-induced apoptosis in colon cancer cells. Idelalisib also synergized with 5-FU or regorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and antitumor effect of idelalisib in xenograft model. These results demonstrate a critical role of PUMA in mediating the anticancer effects of idelalisib in colon cancer cells and suggest that PUMA induction can be used as an indicator of idelalisib sensitivity, and also have important implications for it clinical applications.

Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma

“…Previous studies have focused on the impact of idelalisib on cell cycle checkpoint, which is widely recognized as the primary mode of antitumor therapy 24 . Previous reports indicate that idelalisib enhances apoptosis through the intrinsic apoptotic pathway 12 , 25 . However, the exact mechanism of this activity is still not well-understood, and the role of apoptosis in the therapeutic response to idelalisib is still speculative.…”

“…However, idelalisib has side effects, such as colitis, diarrhea, severe hepatotoxicity, and intestinal perforation 9 , 10 . Idelalisib has also been found to be effective in p53-mutated CLL patients with high-risk genetic traits, which suggests the treatment of p53 deletion/mutant patients should involve screening for idelalisib 11 , 12 . However, the mechanism of autonomous effects of idelalisib, such as cell killing in solid tumors, is unclear.…”

TRAIL, Wnt, Sonic Hedgehog, TGFβ, and miRNA Signalings Are Potential Targets for Oral Cancer Therapy

“…Furthermore, the p53-upregulated modulator of apoptosis (PUMA; BC2 binding component 3; BBC3) may also interact with Akt. For example, anticancer drugs such as idelalisib [ 96 ] and pazopanib [ 97 ] were reported to activate PUMA in colon cancer cells by inhibiting Akt signaling. Accordingly, Akt, STAT3, and PUMA may interact with each other.…”

NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction

“…Treating HCT116 cells with 4 μmol/L NVP-BKM120 significantly increased the protein and mRNA level of PUMA in a time-dependent manner (Figure 2A-2C ). NVP-BKM120 also increased PUMA protein and mRNA level in p53 -Knockdown ( p53 -KD) HCT116 cells [ 17 ] (Figure 2A and 2D ). Moreover, NVP-BKM120 upregulated PUMA expression in p53 -WT Lim2405, LoVo CRC cells, as well as p53 -mutant DLD1, HT29 and SW480 CRC cells (Figure 2E ).…”

“…Furthermore, to examine the function of PUMA in NVP-BKM120-induced apoptosis, we generated PUMA stable knockdown ( PUMA -KD) HCT116 cells [ 17 ]. In PUMA -KD cells, apoptosis was significantly reduced, which was induced by 2-4 μmol/L NVP-BKM120 (Figure 3A ).…”