Summary
Critical regulators of the unfolded protein response (UPR)—IRE1α and PERK— promote adaptation or apoptosis depending on levels of endoplasmic reticulum (ER) stress. While the UPR is activated in many cancers, its effects on tumor growth remain controversial. We used genetic and pharmacologic approaches to modulate IRE1α and PERK in cultured cells and xenograft and spontaneous genetic (RIP-Tag2) mouse models of pancreatic neuroendocrine tumors (PanNETs), highly secretory neoplasms prone to ER stress. We found that UPR signaling is optimized for adaptation and that inhibiting either IRE1α or PERK leads to hyperactivation and apoptotic signaling through the reciprocal arm, halting tumor growth and survival. Our results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers experiencing elevated ER stress.
Significance For the nearly 1,500 Americans diagnosed with PanNETs annually, surgery is the only potentially curative treatment. Unfortunately, the five-year survival is extremely low for the ~25% of patients who develop metastatic disease. Derived from pancreatic endocrine cells, PanNETs universally hypersecrete one or more peptide hormones, likely sensitizing them to ER protein-folding stress. Accordingly, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Importantly, genetic and pharmacological inhibition of the IRE1α or PERK pathways in two preclinical PanNET models led to compensatory hyperactivation of the reciprocal arm and impaired tumor survival and growth. Our results provide new mechanical insight and strong rationale for targeting the UPR in neoplasms with elevated ER stress.
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