Obatoclax, a Pan-BCL-2 Inhibitor, Downregulates Survivin to Induce Apoptosis in Human Colorectal Carcinoma Cells Via Suppressing WNT/β-catenin Signaling

Abstract

Colorectal cancer (CRC) is a highly prevailing cancer and the fourth leading cause of cancer mortality worldwide. Aberrant expression of antiapoptotic BCL-2 family proteins is closely linked to neoplastic progression and chemoresistance. Obatoclax is a clinically developed drug, which binds antiapoptotic BCL-2, BCL-xL, and MCL-1 for inhibition to elicit apoptosis. Survivin is an antiapoptotic protein, whose upregulation correlates with pathogenesis, therapeutic resistance, and poor prognosis in CRC. Herein, we provide the first evidence delineating the functional linkage between Obatoclax and survivin in the context of human CRC cells. In detail, Obatoclax was found to markedly downregulate survivin. This downregulation was mainly achieved via transcriptional repression, as Obatoclax lowered the levels of both survivin mRNA and promoter activity, while blocking proteasomal degradation failed to prevent survivin from downregulation by Obatoclax. Notably, ectopic survivin expression curtailed Obatoclax-induced apoptosis and cytotoxicity, confirming an essential role of survivin downregulation in Obatoclax-elicited anti-CRC effect. Moreover, Obatoclax was found to repress hyperactive WNT/β-catenin signaling activity commonly present in human CRC cells, and, markedly, ectopic expression of dominant-active β-catenin mutant rescued the levels of survivin along with elevated cell viability. We further revealed that, depending on the cell context, Obatoclax suppresses WNT/β-catenin signaling in HCT 116 cells likely via inducing β-catenin destabilization, or by downregulating LEF1 in DLD-1 cells. Collectively, we for the first time define survivin downregulation as a novel, pro-apoptotic mechanism of Obatoclax as a consequence of Obatocalx acting as an antagonist to WNT/β-catenin signaling.

Hypoxia Molecular Characterization in Hepatocellular Carcinoma Identifies One Risk Signature and Two Nomograms for Clinical Management

“…Therefore, the high hypoxia pattern could limit the efficacy of sorafenib, further giving rise to the poor sensitivity of C2 [ 36 ]. Moreover, C2 exhibited more sensitivity to obatoclax, which might be due to obatoclax promoted tumor cells apoptosis by antagonizing WNT/ β -catenin signaling that significantly was enriched in C2 [ 54 ]. In addition, we developed a risk signature termed HARS.…”

MicroRNA-135a-5p Promotes the Functional Recovery of Spinal Cord Injury by Targeting SP1 and ROCK

“…Bcl-2 family members have been shown to play a pivotal role in regulating cell death by acting as critical decision points in the apoptosis pathway. 50 A previous study showed that the overexpression of Bcl-2 suppressed apoptosis following SCI. 24 This finding is in accordance with our results, which showed the upregulation of Bcl-2 after miR-135a-5p transfection ( Figure 3 G).…”

Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/β-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis

“…The luciferase reporter vector for β-catenin-mediated, TCF/LEF-mediated, transcriptional activity M50 Super 8x TOPFlash (Addgene plasmid #12456) and the TOPFlash mutant vector M51 Super 8x FOPFlash (Addgene plasmid #12457) were gifts from Professor Randall Moon. The pBabe-HA–∆N90-β-catenin plasmid, a pBabe-based vector for the ectopic expression of an N-terminal, hemagglutinin (HA) epitope-tagged, dominant–active β-catenin mutant, has been described in detail in our previous report [ 34 ]. Production of pBabe-derived retroviral particles and subsequent infection to target cells was performed according our established protocols [ 35 ].…”