Parallel signaling through IRE1α and PERK regulates pancreatic neuroendocrine tumor growth and survival

Abstract

Master 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 unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNETs) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. For the nearly 1,500 Americans diagnosed with PanNETs annually, surgery is the only potentially curative treatment; however the five-year survival is extremely low for those who develop metastatic disease. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. We then used genetic and pharmacologic approaches to modulate IRE1α and PERK in cultured cells and xenograft and spontaneous genetic (RIP-Tag2) mouse models of PanNETs. 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, thereby 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.SignificanceThe unfolded protein response (UPR) is upregulated in human pancreatic neuroendocrine tumors and its genetic or pharmacological inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in neoplasms with elevated ER stress.

Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib

“…Next, we showed that specific inhibition of the IRE1α kinase domain by KIRA8 was coupled with CHOP expression, which could be associated with PERK activation, whereas selective PERK inhibitors conversely decreased the cell viability with the activation of IRE1α. Similar reciprocal effects of IRE1α–PERK were reported in p-NET [ 17 ]. Thus, in neoplasms driven from professional secretory cells, such as myeloma or β-cells, the balance of IRE1α–PERK activities could be essential for the survival and proliferation of tumors under basal ER stress.…”

“…Recently, we reported that KIRA8 led to the reciprocal hyperactivation of PERK and apoptotic signaling, halting tumor growth and survival during mild ER stress in pancreatic neuroendocrine tumors (p-NET) [ 17 ]. Surprisingly, KIRA8 increased the PERK-related CHOP mRNA expression in a dose-dependent manner in IM-9 cells, as shown in p-NET ( Figure 2 F).…”

Endoplasmic Reticulum Stress Signaling in Cancer Cells

“…Consistent with this notion, human PanNETs were found to have elevated ER stress markers (eg, BiP) and upregulation of homeostatic outputs of the IRE1a and PERK arms of the UPR. 53 More important, rat insulinoma INS-1 cells (a well-established PanNET model) grown in culture have low levels of ER stress and UPR activation; however, the same cells grown in mice as xenografts show marked up-regulation of the UPR, demonstrating that these tumor cells face unique challenges to ER proteostasis in vivo (eg, hypoxia and nutrient deprivation). As such, although loss of IRE1a or PERK had little effect on the growth of INS-1 cells in culture, it markedly halted their ability to form tumors in vivo.…”

“…delivery of the best compound from this series (compound 18 or kinase-inhibiting RNase attenuator 8) showed efficacy in preclinical models of myeloma and pancreatic neuroendocrine tumors. 46,53 A team at GlaxoSmithKline (Brentford, UK) developed highly potent and selective inhibitors of PERK's kinase domain, including GSK2606414 and GSK2656157. 111 Oral administration of GSK2606414 leads to therapeutic doses in the central nervous system and protects against preclinical models of neurodegeneration.…”

Identification of a competing endogenous RNA network associated with prognosis of pancreatic adenocarcinoma

“…The result showed that those mRNAs were enriched in endoplasmic reticulum (ER) stress. Study had shown that both ER stress and fold-protein response are up-regulated in pancreatic neuroendocrine tumors, which can be used as therapeutic targets for pancreatic tumors [32,33]. Moreover, these mRNAs were also enriched in the response to the nutrient levels pathway and peptide metabolic process pathway.…”