Polyphenols elicit antitumor activities, in part, through the induction of anti- or
pro-oxidant effects in
cancer cells which promote priming of protective anti-
tumor immunity. We recently characterized a
polyphenol-rich extract from Caesalpinia spinosa (P2Et) that stimulates in vivo antitumor responses against breast and
melanoma tumor models via the promotion of immunogenic
cancer cell death (ICD). However, the primary mediators whereby P2Et promotes ICD remained unknown. Here, we sought to elucidate the role that severe endoplasmic reticulum (ER) stress plays in mediating P2Et-induced apoptosis and ICD in murine
melanoma cells. Our findings demonstrate a substantial selective induction of specific ER-stress mediators in B16-F10
melanoma cells treated with P2Et. While knockout of the ER stress-associated PKR-like ER
kinase (PERK) prevented induction of apoptosis and expression of ICD markers in P2Et-treated cells, deletion of
X-box binding protein 1 (Xbp1) did not. P2Et-driven activation of PERK in
melanoma cells was found to promote ER-
calcium release, disrupt mitochondrial membrane potential, and trigger upregulation of ICD drivers, surface
calreticulin expression, and extracellular release of
ATP and
HMGB1. Notably,
calcium release inhibition, but not targeting of PERK-driven integrated stress responses, prevented P2Et-induced apoptosis. Collectively, these results underline the central role of PERK-directed
calcium release in mediating the antitumor and immunogenic actions of P2Et in
melanoma cells.