Proteostasis disruption under hypoxia: therapeutic targets in cancer and neurodegenerative diseases
Abstract
Proteostasis, the integrated network regulating protein synthesis, folding, trafficking, and degradation, is essential for cellular function and organismal health. Reduced oxygen availability disrupts proteostasis through increased reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, impaired ATP-dependent protein folding, and altered chaperone expression. In cancer, tumor cells exploit chronic unfolded protein response (UPR) signaling to enhance survival, angiogenesis, and therapeutic resistance. Inhibition of IRE1α and PERK pathways has shown efficacy in preclinical models, though clinical translation faces challenges including off-target toxicity. In neurodegenerative diseases—Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis—chronic hypoxia accelerates protein aggregate accumulation through oxidative modifications and impaired autophagy-lysosome function. Therapeutic strategies targeting γ-secretase, BACE1, and protein clearance pathways have demonstrated limited clinical success despite mechanistic rationale. Understanding hypoxia-induced proteostasis failure may inform therapeutic development, though significant obstacles remain in translating preclinical findings to effective treatments for cancer and neurodegenerative diseases.
References
Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem. 2013;82: 323-355. https://doi.org/10.1146/annurev-biochem-060208-092442
Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol. 2019;20: 421-435. https://doi.org/10.1038/s41580-019-0101-y
Balchin D, Hayer-Hartl M, Hartl FU. In vivo aspects of protein folding and quality control. Science (1979). 2016;353: aac4354. https://doi.org/10.1126/science.aac4354
Alberti S, Hyman AA. Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat Rev Mol Cell Biol. 2021;22: 196-213. https://doi.org/10.1038/s41580-020-00326-6
Badawi Y, Shi H. Relative contribution of prolyl hydroxylase-dependent and -independent degradation of HIF-1alpha by proteasomal pathways in cerebral ischemia. Front Neurosci. 2017;11: 239. https://doi.org/10.3389/fnins.2017.00239
Nelson D, Cox M. Lehninger Biochemie. 3rd ed. Berlin, Germany: Springer; 2005.
Kulak NA, Geyer PE, Mann M. Loss-less nano-fractionator for high sensitivity, high coverage proteomics. Mol Cell Proteomics. 2017;16: 694-705. https://doi.org/10.1074/mcp.O116.065136
Gomez-Pastor R, Burchfiel ET, Thiele DJ. Regulation of heat shock transcription factors and their roles in physiology and disease. Nat Rev Mol Cell Biol. 2018;19: 4-19. https://doi.org/10.1038/nrm.2017.73
Li Y, Li S, Wu H. Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress. Cells. 2022;11: 851. https://doi.org/10.3390/cells11050851
Fregno I, Molinari M. Proteasomal and lysosomal clearance of faulty secretory proteins: ER-associated degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD) pathways. Crit Rev Biochem Mol Biol. 2019;54: 153-163. https://doi.org/10.1080/10409238.2019.1610351
Robinson PJ, Bulleid NJ. Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway. Cells. 2020;9: 1994. https://doi.org/10.3390/cells9091994
Penke B, Bogár F, Crul T, Sántha M, Tóth ME, Vígh L. Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions. Int J Mol Sci. 2018;19: 325. https://doi.org/10.3390/ijms19010325
Woerner AC, Frottin F, Hornburg D, Feng LR, Meissner F, Patra M, et al. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science (1979). 2016;351: 173-176. https://doi.org/10.1126/science.aad2033
Balch WE, Morimoto RI, Dillin A, Kelly JW. Adapting proteostasis for disease intervention. Science (1979). 2008;319: 916-919. https://doi.org/10.1126/science.1141448
Kaufman DM, Wu X, Scott BA, Itani OA, Van Gilst MR, Bruce JE, et al. Ageing and hypoxia cause protein aggregation in mitochondria. Cell Death Differ. 2017;24: 1730-1738. https://doi.org/10.1038/cdd.2017.101
Agrawal A, Rathor R, Suryakumar G. Oxidative protein modification alters proteostasis under acute hypobaric hypoxia in skeletal muscles: a comprehensive in vivo study. Cell Stress Chaperones. 2017;22: 429-443. https://doi.org/10.1007/s12192-017-0795-8
Díaz-Villanueva J, Díaz-Molina R, García-González V. Protein Folding and Mechanisms of Proteostasis. Int J Mol Sci. 2015;16: 17193-17230. https://doi.org/10.3390/ijms160817193
Sučec I, Bersch B, Schanda P. How do Chaperones Bind (Partly) Unfolded Client Proteins? Front Mol Biosci. 2021;8. https://doi.org/10.3389/fmolb.2021.762005
Teodoro RO, O'Farrell PH. Nitric oxide-induced suspended animation promotes survival during hypoxia. EMBO J. 2003;22: 580-587. https://doi.org/10.1093/emboj/cdg070
Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg Nahum and Koromilas A, et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol. 2002;22: 7405-7416. https://doi.org/10.1128/MCB.22.21.7405-7416.2002
Gromley C. Characterization of neuronal specific responses to induced misfolded protein stress in Caenorhabditis elegans. James Madison University. 2017.
Wen Y, Hu J, Wang J, Liu X, Li S, Luo Y. Effect of glycolysis and heat shock proteins on hypoxia adaptation of Tibetan sheep at different altitude. Gene. 2021;803: 145893. https://doi.org/10.1016/j.gene.2021.145893
Xu H. Cochaperones enable Hsp70 to use ATP energy to stabilize native proteins out of the folding equilibrium. Sci Rep. 2018;8: 13213. https://doi.org/10.1038/s41598-018-31641-w
Chaudhary P, Suryakumar G, Prasad R, Singh SN, Ali S, Ilavazhagan G. Effect of acute hypobaric hypoxia on skeletal muscle protein turnover . Al Ameen Journal Medical Science. 2012;5: 355-361.
Oakes SA. Endoplasmic reticulum proteostasis: a key checkpoint in cancer. American Journal of Physiology-Cell Physiology. 2017;312: C93-C102. https://doi.org/10.1152/ajpcell.00266.2016
Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2013;1833: 3460-3470. https://doi.org/10.1016/j.bbamcr.2013.06.028
Shimoda LA, Undem C. Interactions between calcium and reactive oxygen species in pulmonary arterial smooth muscle responses to hypoxia. Respir Physiol Neurobiol. 2010;174: 221-229. https://doi.org/10.1016/j.resp.2010.08.014
Bartoli M, Richard I. Calpains in muscle wasting. Int J Biochem Cell Biol. 2005;37: 2115-2133. https://doi.org/10.1016/j.biocel.2004.12.012
Dufey E, Urra H, Hetz C. ER proteostasis addiction in cancer biology: Novel concepts. Semin Cancer Biol. 2015;33: 40-47. https://doi.org/10.1016/j.semcancer.2015.04.003
Cross BCS, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc Natl Acad Sci U S A. 2012;109: E869-E878. https://doi.org/10.1073/pnas.1115623109
Wang L, Perera BGK, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, et al. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nat Chem Biol. 2012;8: 982-989. https://doi.org/10.1038/nchembio.1094
Ghosh R, Wang L, Wang ES, Perera BGK, Igbaria A, Morita S, et al. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014;158: 534-548. https://doi.org/10.1016/j.cell.2014.07.002
Atkins C, Liu Q, Minthorn E, Zhang S-Y, Figueroa DJ, Moss K, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013;73: 1993-2002. https://doi.org/10.1158/0008-5472.CAN-12-3109
Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, et al. Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice. Sci Transl Med. 2013;5. https://doi.org/10.1126/scitranslmed.3006767
Kalaria RN, Ihara M. Dementia: Vascular and neurodegenerative pathways-will they meet? Nat Rev Neurol. 2013;9: 487-488. https://doi.org/10.1038/nrneurol.2013.164
Adav SS, Sze SK. Hypoxia-induced Degenerative Protein Modifications associated with aging and age-associated disorders. Aging Dis. 2020;11: 341-364. https://doi.org/10.14336/AD.2019.0604
Wolfe MS. γ-Secretase as a Target for Alzheimer's Disease. Current State of Alzheimer's Disease Research and Therapeutics. Elsevier; 2012. pp. 127-153. https://doi.org/10.1016/B978-0-12-394816-8.00004-0
Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, O'Connor T, et al. β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis. The Journal of Neuroscience. 2007;27: 3639-3649. https://doi.org/10.1523/JNEUROSCI.4396-06.2007
Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer's disease. N Engl J Med. 2018;378(18):1691-1703. https://doi.org/10.1056/NEJMoa1706441
Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, et al. Randomized trial of verubecestat for prodromal Alzheimer's disease. N Engl J Med. 2019;380(15):1408-1420. https://doi.org/10.1056/NEJMoa1812840
Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC. Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin. 2014;30(10):2021-2032. https://doi.org/10.1185/03007995.2014.939167
Moussa-Pacha NM, Abdin SM, Omar HA, Alniss H, Al-Tel TH. BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease. Med Res Rev. 2020;40(1):339-384. https://doi.org/10.1002/med.21622
Mullard A. BACE failures lower AD expectations, again. Nat Rev Drug Discov. 2018;17(6):385. https://doi.org/10.1038/nrd.2018.94
Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73-88. https://doi.org/10.1038/s41582-018-0116-6
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):280-292. https://doi.org/10.1016/j.jalz.2011.03.003
Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann Neurol. 1997;41(1):17-24. https://doi.org/10.1002/ana.410410106
Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207-216. https://doi.org/10.1016/S1474-4422(12)70291-0
Karran E, De Strooper B. The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem. 2016;139 Suppl 2:237-252. https://doi.org/10.1111/jnc.13632
Morris GP, Clark IA, Vissel B. Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease. Acta Neuropathol. 2018;136(5):663-689. https://doi.org/10.1007/s00401-018-1918-8
Yan R, Vassar R. Targeting the β secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol. 2014;13(3):319-329. https://doi.org/10.1016/S1474-4422(13)70276-X
Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9(12):1520-1525. https://doi.org/10.1038/nn1797
De Strooper B, Karran E. The cellular phase of Alzheimer's disease. Cell. 2016;164(4):603-615. https://doi.org/10.1016/j.cell.2015.12.056
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362-381. https://doi.org/10.1097/NEN.0b013e31825018f7
Ferreira D, Nordberg A, Westman E. Biological subtypes of Alzheimer disease: A systematic review and meta-analysis. Neurology. 2020;94(10):436-448. https://doi.org/10.1212/WNL.0000000000009058
Sperling RA, Rentz DM, Johnson KA, Karlawish J, Donohue M, Salmon DP, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med. 2014;6(228):228fs13. https://doi.org/10.1126/scitranslmed.3007941
Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer's disease drug development pipeline: 2020. Alzheimers Dement (N Y). 2020;6(1):e12050. https://doi.org/10.1002/trc2.12050
Cummings J, Ritter A, Zhong K. Clinical trials for disease-modifying therapies in Alzheimer's disease: a primer, lessons learned, and a blueprint for the future. J Alzheimers Dis. 2018;64(s1):S3-S22. https://doi.org/10.3233/JAD-179901
Hampel H, Toschi N, Babiloni C, Baldacci F, Black KL, Bokde ALW, et al. Revolution of Alzheimer precision neurology. Passageway of systems biology and neurophysiology. J Alzheimers Dis. 2018;64(s1):S47-S105. https://doi.org/10.3233/JAD-179932
Copyright (c) 2025 Authors
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
