Autophagy activation by dietary piceatannol enhances the efficacy of immunogenic chemotherapy

Abstract

Immunogenic cell death (ICD) promotes the immune antitumor response via releasing damage-associated molecular patterns (DAMPs) from dying tumor cells. The induction of autophagy improves the efficacy of multiple immunogenic chemotherapies. Here, we show that piceatannol, a dietary phenolic compound that is widely distributed in multiple fruits and vegetables such as grapes, blueberries, and mushrooms, induces autophagy and enhances oxaliplatin (OXA)-induced anticancer immune response. Specifically, piceatannol enhanced OXA-induced release of DAMPs, several key hallmarks of ICD including ATP release, cell surface exposure of calreticulin, and high-mobility group box 1 (HMGB1) release. Mechanistically, piceatannol promoted autophagy via activating TFEB/TFE3, two key transcription factors of the autophagy-lysosome pathway, and inhibiting autophagy attenuated piceatannol plus OXA-induced ATP release. Furthermore, piceatannol induced endoplasmic reticulum stress, which is critical for its role in enhancing OXA-induced cell surface exposure of calreticulin, another key hallmark of ICD. Consistently, the combination of piceatannol with OXA promoted the anticancer effects in immunocompetent mice. Taken together, our results indicate the importance and great potential of dietary piceatannol in cancer immunotherapy. Therefore, piceatannol may be used as an ICD enhancer that improves the efficacy of chemotherapeutics such as OXA in cancer treatment with minimized toxicity.

A single-cell landscape of triptolide-associated testicular toxicity in mice

“…qPCR and western blotting were conducted according to previous protocols [ [30] , [31] , [32] ], and primers for PCR are listed in Table S1 .…”

Natural products in attenuating renal inflammation via inhibiting the NLRP3 inflammasome in diabetic kidney disease

“…It is mainly found in grapes, sugar cane, white tea, rhubarb, passion fruit and blueberries (186). Piceatannol is considered to have anticancer, anti-atherogenic, antioxidative, anti-inflammatory, anti-microbial and estrogenic activities, and is widely used in the treatment of heart disease, leukemia and cancer (187)(188)(189)(190). Yao et al found that piceatannol can inhibit apoptosis, inflammation and oxidative stress of podocytes under HG condition.…”

R(h)oad to antitumour therapy

“…7 In their letter to the editor, Yang et al propose that pharmacological enhancement in the autophagy process can be effective in boosting anticancer immune responses to ICD drugs. 8,9 They propose that ginsenoside Rh2 (G-Rh2) heightened the mitoxantrone (MTX)-induced ICD including adenosine triphosphate (ATP) release increase, discharge of high mobility group box 1 (HMGB1) and repositioning of calreticulin (CALR) to the membrane enhancing anti-tumour immune responses (Figure 1). G-Rh2 are ginsenosides, the main components from ginseng and proved to have pharmacological anti-cancer capabilities, inducing autophagy by activating transcriptional factors…”