Pro-Survival Factor EDEM3 Confers Therapy Resistance in Prostate Cancer

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Jul 28

PMID 35897761

Authors

Emma Scott

Rebecca Garnham

Kathleen Cheung

Adam Duxfield

David J Elliott

Jennifer Munkley

Affiliations

Soon will be listed here.

Abstract

Prostate cancer is the most common cancer in men, and it is primarily driven by androgen steroid hormones. The glycosylation enzyme EDEM3 is controlled by androgen signalling and is important for prostate cancer viability. EDEM3 is a mannosidase that trims mannose from mis-folded glycoproteins, tagging them for degradation through endoplasmic reticulum-associated degradation. Here, we find that is upregulated in prostate cancer, and this is linked to poorer disease-free survival. Depletion of EDEM3 from prostate cancer cells induces an ER stress transcriptomic signature, and EDEM3 overexpression is cyto-protective against ER stressors. expression also positively correlates with genes involved in the unfolded protein response in prostate cancer patients, and its expression can be induced through exposure to radiation. Importantly, the overexpression of EDEM3 promotes radio-resistance in prostate cancer cells and radio-resistance can be reduced through depletion of EDEM3. Our data thus implicate increased levels of EDEM3 with a role in prostate cancer pathology and reveal a new therapeutic opportunity to sensitise prostate tumours to radiotherapy.

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References

Kim K, Moretti L, Mitchell L, Jung D, Lu B . Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2alpha in caspase-3/7-deficient cells. Oncogene. 2010; 29(22):3241-51. PMC: 2953962. DOI: 10.1038/onc.2010.74. View

Barfeld S, East P, Zuber V, Mills I . Meta-analysis of prostate cancer gene expression data identifies a novel discriminatory signature enriched for glycosylating enzymes. BMC Med Genomics. 2015; 7:513. PMC: 4351903. DOI: 10.1186/s12920-014-0074-9. View

Salaroglio I, Panada E, Moiso E, Buondonno I, Provero P, Rubinstein M . PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy. Mol Cancer. 2017; 16(1):91. PMC: 5427528. DOI: 10.1186/s12943-017-0657-0. View

Dube D, Bertozzi C . Glycans in cancer and inflammation--potential for therapeutics and diagnostics. Nat Rev Drug Discov. 2005; 4(6):477-88. DOI: 10.1038/nrd1751. View

Gill C, Walsh S, Morrissey C, Fitzpatrick J, Watson R . Resveratrol sensitizes androgen independent prostate cancer cells to death-receptor mediated apoptosis through multiple mechanisms. Prostate. 2007; 67(15):1641-53. DOI: 10.1002/pros.20653. View

Wek R, Cavener D . Translational control and the unfolded protein response. Antioxid Redox Signal. 2007; 9(12):2357-71. DOI: 10.1089/ars.2007.1764. View

Munkley J, Li L, Krishnan S, Hysenaj G, Scott E, Dalgliesh C . Androgen-regulated transcription of drives alternative splicing patterns in prostate cancer. Elife. 2019; 8. PMC: 6788855. DOI: 10.7554/eLife.47678. View

Amoroso F, Glass K, Singh R, Liberal F, Steele R, Maguire S . Modulating the unfolded protein response with ONC201 to impact on radiation response in prostate cancer cells. Sci Rep. 2021; 11(1):4252. PMC: 7896060. DOI: 10.1038/s41598-021-83215-y. View

Varambally S, Yu J, Laxman B, Rhodes D, Mehra R, Tomlins S . Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell. 2005; 8(5):393-406. DOI: 10.1016/j.ccr.2005.10.001. View

10.

Pinho S, Reis C . Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer. 2015; 15(9):540-55. DOI: 10.1038/nrc3982. View

11.

Munkley J, Oltean S, Vodak D, Wilson B, Livermore K, Zhou Y . The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer. Oncotarget. 2015; 6(33):34358-74. PMC: 4741458. DOI: 10.18632/oncotarget.6024. View

12.

Hirao K, Natsuka Y, Tamura T, Wada I, Morito D, Natsuka S . EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J Biol Chem. 2006; 281(14):9650-8. DOI: 10.1074/jbc.M512191200. View

13.

Madden E, Logue S, Healy S, Manie S, Samali A . The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance. Biol Cell. 2018; 111(1):1-17. DOI: 10.1111/boc.201800050. View

14.

Chern Y, Wong J, Cheng G, Yu A, Yin Y, Schaeffer D . The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer. Cell Death Dis. 2019; 10(7):504. PMC: 6594974. DOI: 10.1038/s41419-019-1687-x. View

15.

Shah S, Rodriguez G, Musick A, Walters W, de Cordoba N, Barbarite E . Targeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR). Cancers (Basel). 2019; 11(2). PMC: 6406669. DOI: 10.3390/cancers11020159. View

16.

Guerriero C, Brodsky J . The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiol Rev. 2012; 92(2):537-76. PMC: 4162396. DOI: 10.1152/physrev.00027.2011. View

17.

Mungrue I, Pagnon J, Kohannim O, Gargalovic P, Lusis A . CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol. 2008; 182(1):466-76. PMC: 2846782. DOI: 10.4049/jimmunol.182.1.466. View

18.

Morgan M, Lawrence T . Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways. Clin Cancer Res. 2015; 21(13):2898-904. PMC: 4494107. DOI: 10.1158/1078-0432.CCR-13-3229. View

19.

Taylor B, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver B . Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010; 18(1):11-22. PMC: 3198787. DOI: 10.1016/j.ccr.2010.05.026. View

20.

Jung Y, Lim E, Heo J, Kwon T, Kim Y . Tunicamycin sensitizes human prostate cells to TRAIL-induced apoptosis by upregulation of TRAIL receptors and downregulation of cIAP2. Int J Oncol. 2012; 40(6):1941-8. DOI: 10.3892/ijo.2012.1402. View