Overexpression of carbonyl reductase 1 in ovarian cancer cells suppresses proliferation and activates the eIF2 signaling pathway

Kadonosawa,Yuka; Yokoyama,Minako; Tatara,Yota; Fujita,Toshitsugu; Yokoyama,Yoshihito

doi:10.3892/ol.2024.14492

Overexpression of carbonyl reductase 1 in ovarian cancer cells suppresses proliferation and activates the eIF2 signaling pathway

Authors:
- Yuka Kadonosawa
- Minako Yokoyama
- Yota Tatara
- Toshitsugu Fujita
- Yoshihito Yokoyama
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan, Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan, Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan
Published online on: June 5, 2024 https://doi.org/10.3892/ol.2024.14492
Article Number: 359
Copyright: © Kadonosawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

High expression of carbonyl reductase 1 (CBR1) protein in ovarian cancer cells inhibits tumor growth and metastasis. However, the underlying mechanism is unknown. To investigate the mechanism by which CBR1 suppresses tumor growth, the present study generated ovarian cancer cells that constitutively overexpress human CBR1 (hCBR1) protein. Ovarian cancer cell lines (OVCAR‑3 and SK‑OV‑3) were transfected with a plasmid encoding hCBR1, followed by selection with G418 to isolate hCBR1‑overexpressing lines. The proliferation rates of hCBR1‑overexpressing cells were then compared with those of negative control and wild‑type cells. Overexpression of hCBR1 led to significant inhibition of proliferation (P<0.05). Subsequently, to investigate changes in intracellular signaling pathways, cellular proteins were extracted and subjected to proteome analysis using liquid chromatography followed by mass spectrometry. There was an inverse correlation between CBR1 protein expression and cell proliferation. In addition, Ingenuity Pathway Analysis of hCBR1‑overexpressing cell lines was performed, which revealed changes in the expression of proteins involved in signaling pathways related to growth regulation. Of these, the eukaryotic translation initiation factor 2 (eIF2) signaling pathway was upregulated most prominently. Thus, alterations in multiple tumor‑related signaling pathways, including eIF2 signaling, may lead to growth suppression. Taken together, the present data may lead to the development of new drugs that target CBR1 and related signaling pathways, thereby improving outcomes for patients with ovarian cancer.

View Figures

View References

1	Mindnich RD and Penning TM: Aldo-keto reductase (AKR) superfamily: Genomics and annotation. Hum Genomics. 3:362–370. 2009. View Article : Google Scholar : PubMed/NCBI
2	Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, et al: Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 13:397–406. 2014. View Article : Google Scholar : PubMed/NCBI
3	Wermuth B, Bohren KM, Heinemann G, von Wartburg JP and Gabbay KH: Human carbonyl reductase. Nucleotide sequence analysis of a cDNA and amino acid sequence of the encoded protein. J Biol Chem. 263:16185–16188. 1988. View Article : Google Scholar : PubMed/NCBI
4	Umemoto M, Yokoyama Y, Sato S, Tsuchida S, Al-Mulla F and Saito Y: Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer. Br J Cancer. 85:1032–1036. 2001. View Article : Google Scholar : PubMed/NCBI
5	Osawa Y, Yokoyama Y, Shigeto T, Futagami M and Mizunuma H: Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation. Int J Oncol. 46:1252–1258. 2015. View Article : Google Scholar : PubMed/NCBI
6	Miura R, Yokoyama Y, Shigeto T, Futagami M and Mizunuma H: Inhibitory effect of carbonyl reductase 1 on ovarian cancer growth via tumor necrosis factor receptor signaling. Int J Oncol. 47:2173–2180. 2015. View Article : Google Scholar : PubMed/NCBI
7	Nishimoto Y, Murakami A, Sato S, Kajimura T, Nakashima K, Yakabe K, Sueoka K and Sugino N: Decreased carbonyl reductase 1 expression promotes tumor growth via epithelial mesenchymal transition in uterine cervical squamous cell carcinomas. Reprod Med Biol. 17:173–181. 2018. View Article : Google Scholar : PubMed/NCBI
8	Kajimura T, Sato S, Murakami A, Hayashi-Okada M, Nakashima K, Sueoka K and Sugino N: Overexpression of carbonyl reductase 1 inhibits malignant behaviors and epithelial mesenchymal transition by suppressing TGF-β signaling in uterine leiomyosarcoma cells. Oncol Lett. 18:1503–1512. 2019.PubMed/NCBI
9	Takenaka K, Ogawa E, Oyanagi H, Wada H and Tanaka F: Carbonyl reductase expression and its clinical significance in non-small-cell lung cancer. Cancer Epidemiol Biomarkers Prev. 14:1972–1975. 2005. View Article : Google Scholar : PubMed/NCBI
10	Graves PR and Haystead TA: Molecular biologist's guide to proteomics. Microbiol Mol Biol Rev. 66:39–63. 2002. View Article : Google Scholar : PubMed/NCBI
11	Chandramouli K and Qian PY: Proteomics: Challenges, techniques and possibilities to overcome biological sample complexity. Hum Genomics Proteomics. 8:2392042009.PubMed/NCBI
12	Wang D, Eraslan B, Wieland T, Hallström B, Hopf T, Zolg DP, Zecha J, Asplund A, Li LH, Meng C, et al: A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Mol Syst Biol. 15:e85032019. View Article : Google Scholar : PubMed/NCBI
13	Martínez-Rodríguez F, Limones-González JE, Mendoza-Almanza B, Esparza-Ibarra EL, Gallegos-Flores PI, Ayala-Luján JL, Godina-González S, Salinas E and Mendoza-Almanza G: Understanding cervical cancer through proteomics. Cells. 10:18542021. View Article : Google Scholar : PubMed/NCBI
14	Shigeto T, Yokoyama Y, Xin B and Mizunuma H: Peroxisome proliferator-activated receptor α and γ ligands inhibit the growth of human ovarian cancer. Oncol Rep. 18:833–840. 2007.PubMed/NCBI
15	Wakui M, Yokoyama Y, Wang H, Shigeto T, Futagami M and Mizunuma H: Efficacy of a methyl ester of 5-aminolevulinic acid in photodynamic therapy for ovarian cancers. J Cancer Res Clin Oncol. 136:1143–1150. 2010. View Article : Google Scholar : PubMed/NCBI
16	Cebulla J, Huuse EM, Pettersen K, van der Veen A, Kim E, Andersen S, Prestvik WS, Bofin AM, Pathak AP, Bjørkøy G, et al: MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity. Br J Cancer. 112:504–513. 2015. View Article : Google Scholar : PubMed/NCBI
17	Zalewski M, Kulbacka J, Saczko J, Drag-Zalesinska M and Choromanska A: Valspodar-modulated chemotherapy in human ovarian cancer cells SK-OV-3 and MDAH-2774. Bosn J Basic Med Sci. 19:234–241. 2019.PubMed/NCBI
18	Lu T, Tang J, Shrestha B, Heath BR, Hong L, Lei YL, Ljungman M and Neamati N: Up-regulation of hypoxia-inducible factor antisense as a novel approach to treat ovarian cancer. Theranostics. 10:6959–6976. 2020. View Article : Google Scholar : PubMed/NCBI
19	Ohgane K and Yoshioka H: Quantification of gel bands by an image J Macro, Band/Peak Quantification Tool v1. Protocols.io. 2019.doi:/10.17504/protocols.io.7vghn3w.
20	Yokoyama M, Fujita T, Kadonosawa Y, Tatara Y, Motooka D, Ikawa M, Fujii H and Yokoayama Y: Development of transgenic mice overexpressing mouse carbonyl reductase 1. Mol Biol Rep. 50:531–540. 2023. View Article : Google Scholar : PubMed/NCBI
21	Costantini LM, Fossati M, Francolini M and Snapp EL: Assessing the tendency of fluorescent proteins to oligomerize under physiologic conditions. Traffic. 13:643–649. 2013. View Article : Google Scholar
22	Boye E and Grallert B: eIF2α phosphorylation and the regulation of translation. Curr Genet. 66:293–297. 2020. View Article : Google Scholar : PubMed/NCBI
23	Johnston GC, Pringle JR and Hartwell LH: Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. Exp Cell Res. 105:79–98. 1977. View Article : Google Scholar : PubMed/NCBI
24	Kovalski JR, Kuzuoglu-Ozturk D and Ruggero D: Protein synthesis control in cancer: selectivity and therapeutic targeting. EMBO J. 41:e1098232022. View Article : Google Scholar : PubMed/NCBI
25	Clemens MJ and Bommer UA: Translational control: The cancer connection. Int J Biochem Cell Biol. 31:1–23. 1999. View Article : Google Scholar : PubMed/NCBI
26	Hinnebusch AG: Molecular mechanism of scanning and start codon selection in eukaryotes. Microbiol Mol Biol Rev. 75:434–467. 2011. View Article : Google Scholar : PubMed/NCBI
27	Harris AL: Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer. 2:38–47. 2002. View Article : Google Scholar : PubMed/NCBI
28	Hinnebusch AG: The scanning mechanism of eukaryotic translation initiation. Annu Rev Biochem. 83:779–812. 2014. View Article : Google Scholar : PubMed/NCBI
29	Gandin V, Masvidal L, Cargnello M, Gyenis L, McLaughlan S, Cai Y, Tenkerian C, Morita M, Balanathan P, Jean-Jean O, et al: mTORC1 and CK2 coordinate ternary and eIF4F complex assembly. Nat Commun. 7:111272016. View Article : Google Scholar : PubMed/NCBI
30	Wengrod J, Wang D, Weiss S, Zhong H, Osman I and Gardner LB: Phosphorylation of eIF2α triggered by mTORC1 inhibition and PP6C activation is required for autophagy and is aberrant in PP6C-mutated melanoma. Sci Signal. 8:ra272015. View Article : Google Scholar : PubMed/NCBI