Antitumor activity of HPA3P through RIPK3-dependent regulated necrotic cell death in colon cancer

The antimicrobial peptide HPA3 shows anticancer activity in gastric cancer and leukaemia. However, how HPA3 exerts its anticancer activity, as well as whether it also exhibits activity in other cancers, remains unknown. Therefore, the aim of this study was to evaluate the anticancer activity of HPA3 and its analogues in colon cancer and to elucidate the mechanisms responsible for this activity. HPA3P decreased cell viability, whereas HPA3 and HPA3P2 did not decrease cell viability in colon cancer cells compared with control cells. This reduction in cell viability occurred through necrosis, a conclusion supported by our observation of the release of cellular contents, our intracellular PI staining results, and our observation of the release of HMGB1. Moreover, RIPK3 inhibition blocks the reduction of cell viability by HPA3P. Consistent with this finding, we found that knocking down RIPK3 and MLKL, key necroptosis proteins, attenuates the reductions in cell viability induced by HPA3P. Furthermore, HPA3P can improve the anticancer activity of chemotherapeutic agents and exhibits anticancer activity in other cancer cells. These results suggest that HPA3P may have potential as an anticancer agent in the treatment of colon cancer.