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.
Highlights
Colorectal cancer (CRC) is the second and third most common cancer diagnosed in women and men, respectively, and is the fourth leading cause of cancer death worldwide [1]
Inactivated mutations in the APC gene or activating mutations in the β-catenin-encoding gene CTNNB1 together account for the majority of genetic lesions in CRC cells, which lead to stabilization and ensuing nuclear translocation of β-catenin to facilitate TCF/LEF-dependent transcription of WNT/β-catenin signaling target genes to drive cell proliferation, metastasis, and cancer stemness [6,7,8]
A well-defined WNT/β-catenin target gene [10], is the smallest member of the inhibitor of apoptosis (IAP) protein family and, of note, is the fourth most elevated mRNA in the human cancer transcriptome while it is barely detected in normal adult cells [11,12]
Summary
Colorectal cancer (CRC) is the second and third most common cancer diagnosed in women and men, respectively, and is the fourth leading cause of cancer death worldwide [1]. It is generally believed that hyperactive β-catenin-mediated transcriptional activation underlies the initiation and malignant progression of CRC; components in the WNT/β-catenin signaling pathway represent promising molecular targets for CRC therapeutics [6,9]. A well-defined WNT/β-catenin target gene [10], is the smallest member of the inhibitor of apoptosis (IAP) protein family and, of note, is the fourth most elevated mRNA in the human cancer transcriptome while it is barely detected in normal adult cells [11,12]. A synthetic derivative of bacterial prodiginines [21], is a clinically developed small-molecule pan-BCL-2 inhibitor that functions by blocking BH3-mediated binding of BH3-only proteins or BAX/BAK to antiapoptotic BCL-2, BCL-xL, and MCL-1, causing BAX/BAK activation to trigger apoptosis [22]. Our novel discovery reveals the multiple modes of Obatoclax’s pharmacological action and the potential application of Obatoclax to CRC therapy
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