Abstract
The antiparasitic drug NTZ inhibits WNT signaling and APC-mutant colorectal cancer cell growth.
Major finding: The antiparasitic drug NTZ inhibits WNT signaling and APC-mutant colorectal cancer cell growth.
Mechanism: NTZ stabilizes PAD2, which promotes β-catenin citrullination and turnover, to block WNT signaling.
Impact: NTZ may effectively inhibit WNT signaling to treat patients with WNT pathway–mutant tumors.
WNT signaling is often activated in colorectal cancer by mutations in APC, making WNT signaling a potential therapeutic target. Active WNT signaling promotes downstream nuclear accumulation of the transcriptional coactivator β-catenin, but when WNT signaling is inactive, β-catenin is degraded in the cytoplasm by the destruction complex (containing APC, AXIN, and GSK3β). The available WNT inhibitors target signaling upstream of the destruction complex, and thus are not suited for treatment of tumors harboring APC or CTNNB1 (which encodes β-catenin) mutations. Qu and colleagues performed a screen of FDA-approved drugs to discover clinically usable WNT/β-catenin signaling inhibitors. This screen identified the antiparasitic drug nitazoxanide (NTZ) as an inhibitor of WNT signaling. APC- and CTNNB1-mutant colorectal cancer cells were sensitive to NTZ treatment in vitro, and NTZ reduced β-catenin expression and the number of tumors in vivo in APCmin/+ mice, which develop spontaneous tumors. NTZ-mediated depletion of β-catenin was independent of GSK3β and APC, indicating that it acts downstream of the β-catenin destruction complex. Mechanistically, NTZ inhibited β-catenin signaling by binding to and stabilizing peptidyl arginine deiminase 2 (PAD2), which catalyzes the conversion of arginine to citrulline in a process called citrullination or deamination. PAD2 bound directly to β-catenin, promoting its citrullination and turnover in colorectal cancer cells, whereas loss of PAD2 enzymatic activity prevented the increase in citrullination and β-catenin turnover. Consistent with these findings, PAD2 expression was sufficient to suppress the growth of WNT-activated colorectal cancer cells. Collectively, these findings identify NTZ as a WNT signaling inhibitor that, in contrast to currently available inhibitors, may be effective in APC- or CTNNB1-mutant tumors. Further, these results suggest that citrullination of β-catenin can control its stability.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
