Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR)

Gehan Botrus, Richard M Miller, Pedro Luiz Serrano Uson Junior, Geoffrey Kannan, Haiyong Han, Daniel D Von Hoff, Gehan Botrus, Richard M Miller, Pedro Luiz Serrano Uson Junior, Geoffrey Kannan, Haiyong Han, Daniel D Von Hoff

Abstract

High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1α, PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death.

Keywords: apoptosis; endoplasmic reticulum (ER) stress; pancreatic cancer; unfolded protein response (UPR).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Unfolded Protein Response. A simplified version of unfolded protein response (UPR). Under stress, cells activate the adaptative UPR to establish cellular homeostasis and proteostasis. The sensors IRE1, PERK, and ATF6 are activated after the dissociation of GRP78, which is recruited due to the accumulation of misfolded and unfolded proteins. IRE1 oligomerization and auto-phosphorylation induce kinase and RNase activity leading to mRNA degradation (RIDD) and altered splicing of the XBP1 mRNA and production of the transcription factor XBP1s. PERK undergoes oligomerization and auto-phosphorylation, subsequently phosphorylating the eukaryotic translation initiation factor eIF2α, resulting in the translation of transcription factor ATF4. NRF2 is also phosphorylated by PERK and activates antioxidant responses. ATF6 activation occurs after transport to the Golgi apparatus where it undergoes S1P/S2P protease cleavage, yielding transcriptionally active ATF6f. The transcriptional events mediated by XBP1s, ATF4, and ATF6f promote the expression of chaperones and components of ER-associated protein degradation (ERAD), reducing protein translation and increasing ER capacity in order to restore homeostasis. Additionally, UPR-mediated gene expression also directly impacts autophagy, cytokine production, and apoptosis. Figure 1 was created with BioRender.com.
Figure 2
Figure 2
Cellular Responses to Prolonged Levels of ER Stress.

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