Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy

Overview

Journal Int J Cell Biol

Publisher Wiley

Specialty Cell Biology

Date 2010 Feb 11

PMID 20145727

Citations 166

Authors

Tom Verfaillie

Maria Salazar

Guillermo Velasco

Patrizia Agostinis

Affiliations

Soon will be listed here.

Abstract

Different physiological and pathological conditions can perturb protein folding in the endoplasmic reticulum, leading to a condition known as ER stress. ER stress activates a complex intracellular signal transduction pathway, called unfolded protein response (UPR). The UPR is tailored essentially to reestablish ER homeostasis also through adaptive mechanisms involving the stimulation of autophagy. However, when persistent, ER stress can switch the cytoprotective functions of UPR and autophagy into cell death promoting mechanisms. Recently, a variety of anticancer therapies have been linked to the induction of ER stress in cancer cells, suggesting that strategies devised to stimulate its prodeath function or block its prosurvival function, could be envisaged to improve their tumoricidial action. A better understanding of the molecular mechanisms that determine the final outcome of UPR and autophagy activation by chemotherapeutic agents, will offer new opportunities to improve existing cancer therapies as well as unravel novel targets for cancer treatment.

Citing Articles

A Novel Approach for In Vitro Testing and Hazard Evaluation of Nanoformulated RyR2-Targeting siRNA Drugs Using Human PBMCs.

Bettinsoli V, Melzi G, Crea A, Degli Esposti L, Iafisco M, Catalucci D Life (Basel). 2025; 15(1).

PMID: 39860035 PMC: 11766699. DOI: 10.3390/life15010095.

Importance of Autophagy in Mediating Cellular Responses to Iron Overload in Cardiomyocytes.

Tam E, Reno C, Nguyen K, Cho S, Sweeney G Rev Cardiovasc Med. 2024; 23(5):167.

PMID: 39077594 PMC: 11273664. DOI: 10.31083/j.rcm2305167.

Thapsigargin and Tunicamycin Block SARS-CoV-2 Entry into Host Cells via Differential Modulation of Unfolded Protein Response (UPR), AKT Signaling, and Apoptosis.

Al Otaibi A, Mubarak S, Al Hejji F, Almasaud A, Al Jami H, Iqbal J Cells. 2024; 13(9.

PMID: 38727305 PMC: 11083125. DOI: 10.3390/cells13090769.

An industrialized diet as a determinant of methylation in the 1F region of the gene promoter.

Dos Santos Vieira T, Freitas F, Neto L, Borcoi A, Mendes S, Olinda A Front Nutr. 2024; 11:1168715.

PMID: 38633601 PMC: 11021719. DOI: 10.3389/fnut.2024.1168715.

The Cytoprotective Role of Autophagy in Response to BRAF-Targeted Therapies.

Elshazly A, Gewirtz D Int J Mol Sci. 2023; 24(19).

PMID: 37834222 PMC: 10572960. DOI: 10.3390/ijms241914774.

References

Bialik S, Kimchi A . The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem. 2006; 75:189-210. DOI: 10.1146/annurev.biochem.75.103004.142615. View

Ding W, Ni H, Gao W, Hou Y, Melan M, Chen X . Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem. 2006; 282(7):4702-4710. DOI: 10.1074/jbc.M609267200. View

Martinet W, Agostinis P, Vanhoecke B, Dewaele M, De Meyer G . Autophagy in disease: a double-edged sword with therapeutic potential. Clin Sci (Lond). 2009; 116(9):697-712. DOI: 10.1042/CS20080508. View

Puthalakath H, OReilly L, Gunn P, Lee L, Kelly P, Huntington N . ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007; 129(7):1337-49. DOI: 10.1016/j.cell.2007.04.027. View

Hanada T, Noda N, Satomi Y, Ichimura Y, Fujioka Y, Takao T . The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem. 2007; 282(52):37298-302. DOI: 10.1074/jbc.C700195200. View

He C, Klionsky D . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009; 43:67-93. PMC: 2831538. DOI: 10.1146/annurev-genet-102808-114910. View

Maytin E, Ubeda M, Lin J, Habener J . Stress-inducible transcription factor CHOP/gadd153 induces apoptosis in mammalian cells via p38 kinase-dependent and -independent mechanisms. Exp Cell Res. 2001; 267(2):193-204. DOI: 10.1006/excr.2001.5248. View

Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K . ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 2002; 16(11):1345-55. PMC: 186318. DOI: 10.1101/gad.992302. View

Korennykh A, Egea P, Korostelev A, Finer-Moore J, Zhang C, Shokat K . The unfolded protein response signals through high-order assembly of Ire1. Nature. 2008; 457(7230):687-93. PMC: 2846394. DOI: 10.1038/nature07661. View

10.

Nawrocki S, Bruns C, Harbison M, Bold R, Gotsch B, Abbruzzese J . Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther. 2003; 1(14):1243-53. View

11.

Gills J, Lopiccolo J, Dennis P . Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy. Autophagy. 2007; 4(1):107-9. DOI: 10.4161/auto.5224. View

12.

Jousse C, Deval C, Maurin A, Parry L, Cherasse Y, Chaveroux C . TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway. J Biol Chem. 2007; 282(21):15851-61. DOI: 10.1074/jbc.M611723200. View

13.

Vicencio J, Ortiz C, Criollo A, Jones A, Kepp O, Galluzzi L . The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death Differ. 2009; 16(7):1006-17. DOI: 10.1038/cdd.2009.34. View

14.

Wang H, Pathan N, Ethell I, Krajewski S, Yamaguchi Y, Shibasaki F . Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science. 1999; 284(5412):339-43. DOI: 10.1126/science.284.5412.339. View

15.

Morris J, Dorner A, Edwards C, Hendershot L, Kaufman R . Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins. J Biol Chem. 1997; 272(7):4327-34. DOI: 10.1074/jbc.272.7.4327. View

16.

Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents N, Arias C . XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell. 2007; 27(1):53-66. DOI: 10.1016/j.molcel.2007.06.011. View

17.

Sakai J, Duncan E, Rawson R, Hua X, Brown M, Goldstein J . Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell. 1996; 85(7):1037-46. DOI: 10.1016/s0092-8674(00)81304-5. View

18.

Wei Y, Pattingre S, Sinha S, Bassik M, Levine B . JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008; 30(6):678-88. PMC: 2478643. DOI: 10.1016/j.molcel.2008.06.001. View

19.

Chauhan D, Hideshima T, Anderson K . Proteasome inhibition in multiple myeloma: therapeutic implication. Annu Rev Pharmacol Toxicol. 2005; 45:465-76. DOI: 10.1146/annurev.pharmtox.45.120403.100037. View

20.

Chami M, Prandini A, Campanella M, Pinton P, Szabadkai G, Reed J . Bcl-2 and Bax exert opposing effects on Ca2+ signaling, which do not depend on their putative pore-forming region. J Biol Chem. 2004; 279(52):54581-9. DOI: 10.1074/jbc.M409663200. View