Abstract
Caspases are well known for their role in apoptosis. Recently, nonapoptotic roles of caspases have been identified, however, these noncanonical roles are not well documented and the mechanisms involved are not fully understood. Here, we studied the role of cleaved caspase-3 using human- and mouse-proficient caspase-3 cancer cell lines and human-deficient caspase-3 cancer cells. Cleaved caspase-3 functioned as a transcription factor and directly bound to DNA. A DNA-binding domain was identified in the small subunit of caspase-3 and an active conformation was essential for caspase-3 transcriptional activity. Caspase-3 DNA binding enhanced angiogenesis by upregulating the expression of proangiogenic genes and by activating pathways that promoted endothelial cell activation. Some proapoptotic genes were downregulated in caspase-3-proficient cells. Inhibiting caspase-3 increased the efficacy of chemotherapy and decreased spontaneous tumor development. These data highlight a novel nonapoptotic role of caspase-3 and suggest that cleaved caspase-3 could be a new therapeutic target in cancer. SIGNIFICANCE: These findings report a noncanonical function of caspase-3 by demonstrating its ability to transcriptionally regulate the VEGFR pathway.
Highlights
Apoptosis is a well-known physiologic process that enables the maintenance of homeostasis in multicellular organisms
As FDG uptake was described as being correlated with tumor angiogenesis [16], we wondered whether the result observed with FDG uptake was linked to tumor blood vessels
To confirm that angiogenesis was impacted by docetaxel and Casp-3 pharmacologic inhibition, we performed RNA sequencing of human MDA-MB-231 injected into nude mice and treated or not with docetaxel Æ the Casp-3 inhibitor Z-DEVD-FMK
Summary
Apoptosis is a well-known physiologic process that enables the maintenance of homeostasis in multicellular organisms. One of the best-known markers of apoptosis is the proteolytic cleavage of pro-caspase-3 into its active form, caspase-3 (Casp-3). Activation of Casp-3 is considered a deleterious event in different pathophysiologic processes, such as. All nonapoptotic roles of Casp-3 rely on its proteolytic activity [6,7,8,9]. We showed that Casp-3 activation induced transcriptional changes, leading to the upregulation of genes involved in angiogenesis and downregulation of genes involved in proapoptotic pathways. We have shown that Casp-3 was able to directly interact with the promoter of various proangiogenic genes, such as VEGFA gene, and induce transcription thanks to a specific DNA-binding domain. The pharmacologic targeting of Casp-3 increased chemotherapy cytotoxicity in cancer cells
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