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

International Journal of Molecular Sciences
Chi-Hung R OrChia-Che Chang

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 prese...Continue Reading

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Citations

Jun 13, 2020·International Journal of Molecular Sciences·Alessandro PassardiPaola Ulivi
Dec 10, 2020·Molecular Therapy. Nucleic Acids·Nanxiang WangLimin Rong
Jul 1, 2020·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Nir Shahar, Sarit Larisch
Aug 20, 2020·European Journal of Pharmacology·Paola C BrancoLeticia V Costa-Lotufo

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Datasets Mentioned

BETA
U75285

Methods Mentioned

BETA
nuclear translocation
PCR
transfection

Key Resources (RRID) Mentioned

Addgene_12456
Addgene_12457

Software Mentioned

ImageJ

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