Current issue
Archive
Manuscripts accepted
About the Journal
Editorial office
Editorial board
Abstracting and indexing
Subscription
Contact
Ethical standards and procedures
Most read articles
Instructions for authors
Article Processing Charge (APC)
Regulations of paying article processing charge (APC)
CLINICAL RESEARCH
RXRA induces endoplasmic reticulum stress via ATP2A3 transcriptional modulation in ovarian cancer cells
1
Department of Clinical Laboratory, Zibo Central Hospital, Zibo, China
2
GeneMind Biosciences Company Limited, ShenZhen, China
3
Department of Clinical Laboratory, Hunan People’s Hospital, Changsha, China
4
School of Life Sciences, Fudan University, Shanghai, China
5
Salus BioMed Company Limited, ShenZhen, China
6
College of Pharmacy, Xiangnan University, Chenzhou, China
7
Department of Blood Transfusion, Zibo Central Hospital, Zibo, China
These authors had equal contribution to this work
Submission date: 2024-08-19
Final revision date: 2024-12-23
Acceptance date: 2025-01-01
Online publication date: 2025-03-04
Corresponding author
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Ovarian cancer (OV) progression involves intricate interactions of genes and cellular pathways, with the ATP2A gene family recently emerging as significant.
Material and methods:
Through bioinformatic analysis, we evaluated the expression and prognostic impact of the ATP2A gene family in various cancers, emphasizing OV. Immunohistochemical and clinical expression profiles of ATP2A2 were subsequently analyzed in OVs. We further explored the effects of ATP2A3 modulation on cellular behaviors, involving proliferation, apoptosis, migration, and invasion in OV cell lines. The function of ATP2A3 in mediating endoplasmic reticulum (ER) stress and its influence on calcium-mediated kinase activities was elucidated. Furthermore, a comprehensive analysis of The Cancer Genome Atlas (TCGA) was conducted, spotlighting the interplay between RXRA and ATP2A3. Finally, their effects on OV cell progression were analyzed in vitro.
Results:
Our results highlighted a consistent association between low expression of ATP2A3 in OV and improved patient prognosis. ATP2A3 regulation has significant effects on the proliferation, apoptosis, migration, and invasion of OV cells. Notably, overexpression of ATP2A3 enhanced ER stress biomarkers but inhibited calcium-mediated kinase activity. At the same time, in vitro cell experiments found that RXRA overexpression can inhibit the malignant behavior of OV cells, and it is positively correlated with ATP2A3. Overexpression of RXRA inhibited OV progression by inducing the ER stress response, which was partially offset by ATP2A3.
Conclusions:
ATP2A3 and RXRA synergistically modulate OV cell behaviors and the ER stress response, revealing prospective therapeutic avenues for OV intervention.
Ovarian cancer (OV) progression involves intricate interactions of genes and cellular pathways, with the ATP2A gene family recently emerging as significant.
Material and methods:
Through bioinformatic analysis, we evaluated the expression and prognostic impact of the ATP2A gene family in various cancers, emphasizing OV. Immunohistochemical and clinical expression profiles of ATP2A2 were subsequently analyzed in OVs. We further explored the effects of ATP2A3 modulation on cellular behaviors, involving proliferation, apoptosis, migration, and invasion in OV cell lines. The function of ATP2A3 in mediating endoplasmic reticulum (ER) stress and its influence on calcium-mediated kinase activities was elucidated. Furthermore, a comprehensive analysis of The Cancer Genome Atlas (TCGA) was conducted, spotlighting the interplay between RXRA and ATP2A3. Finally, their effects on OV cell progression were analyzed in vitro.
Results:
Our results highlighted a consistent association between low expression of ATP2A3 in OV and improved patient prognosis. ATP2A3 regulation has significant effects on the proliferation, apoptosis, migration, and invasion of OV cells. Notably, overexpression of ATP2A3 enhanced ER stress biomarkers but inhibited calcium-mediated kinase activity. At the same time, in vitro cell experiments found that RXRA overexpression can inhibit the malignant behavior of OV cells, and it is positively correlated with ATP2A3. Overexpression of RXRA inhibited OV progression by inducing the ER stress response, which was partially offset by ATP2A3.
Conclusions:
ATP2A3 and RXRA synergistically modulate OV cell behaviors and the ER stress response, revealing prospective therapeutic avenues for OV intervention.
REFERENCES (40)
1.
Gaona-Luviano P, Medina-Gaona LA, Magana-Perez K. Epidemiology of ovarian cancer. Chin Clin Oncol 2020; 9: 47.
2.
Belotti Y, Lim EH, Lim CT. The role of the extracellular matrix and tumor-infiltrating immune cells in the prognostication of high-grade serous ovarian cancer. Cancers 2022; 14: 404.
4.
Morgan RJ Jr, Armstrong DK, Alvarez RD, et al. Ovarian Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2016; 14: 1134-63.
5.
Taylor EC, Irshaid L, Mathur M. Multimodality imaging approach to ovarian neoplasms with pathologic correlation. Radiographics 2021; 41: 289-315.
6.
Mirza MR, Coleman RL, Gonzalez-Martin A, et al. The forefront of ovarian cancer therapy: update on PARP inhibitors. Ann Oncol 2020; 31: 1148-59.
7.
von Gruenigen VE, Huang HQ, Cella D, et al. Quality of life, symptoms and care needs in patients with persistent or recurrent platinum-resistant ovarian cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 2018; 150: 119-26.
8.
Sharma N, Arora S, Saurav S, Motiani RK. Pathophysiological significance of calcium signaling at mitochondria-associated endoplasmic reticulum membranes (MAMs). Curr Opin Physiol 2020; 17: 234-42.
9.
Inagi R. Endoplasmic reticulum stress as a progression factor for kidney injury. Curr Opin Pharmacol 2010; 10: 156-65.
10.
Corazzari M, Gagliardi M, Fimia GM, Piacentini M. Endoplasmic reticulum stress, unfolded protein response, and cancer cell fate. Front Oncol 2017; 7: 78.
11.
Wright MF, Bowdridge E, McDermott EL, et al. Mechanisms of intracellular calcium homeostasis in developing and mature bovine corpora lutea. Biol Reprod 2014; 90: 55.
12.
Kabir MF, Kim HR, Chae HJ. Endoplasmic reticulum stress and autophagy. In: Endoplasmic Reticulum. Catala A (ed.). IntechOpen 2018.
13.
Yan J, Chen S, Zuo Z, He C, Yi M. Graphene oxide quantum dot exposure induces abnormalities in locomotor activities and mechanisms in zebrafish (Danio rerio). J Appl Toxicol 2020; 40: 794-803.
14.
Ronan A, Ingrey A, Murray N, Chee P. Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates acrokeratosis verruciformis of Hopf from the allelic condition Darier disease. Am J Med Genet A 2017; 173: 1975-8.
15.
Zarain-Herzberg A, Garcia-Rivas G, Estrada-Aviles R. Regulation of SERCA pumps expression in diabetes. Cell Calcium 2014; 56: 302-10.
16.
Christodoulou P, Yiallouris A, Michail A, Christodoulou MI, Politis PK, Patrikios I. Altered SERCA expression in breast cancer. Medicina 2021; 57: 1074.
17.
Izquierdo-Torres E, Hernández-Oliveras A, Meneses-Morales I, Rodríguez G, Fuentes-García G, Zarain-Herzberg A. Resveratrol up-regulates ATP2A3 gene expression in breast cancer cell lines through epigenetic mechanisms. Int J Biochem Cell Biol 2019; 113: 37-47
18.
Bachar-Wikstrom E, Wikstrom JD. Darier disease - a multi-organ condition? Acta Derm Venereol 2021; 101: adv00430.
19.
Wang F, Niu Y, Chen K, et al. Extracellular vesicle-packaged circATP2B4 mediates M2 macrophage polarization via miR-532-3p/SREBF1 axis to promote epithelial ovarian cancer metastasis. Cancer Immunol Res 2023; 11: 199-216.
20.
Zhao X, Di Q, Liu H, et al. MEF2C promotes M1 macrophage polarization and Th1 responses. Cell Mol Immunol 2022; 19: 540-53.
21.
Zhou Y, Lin F, Wan T, et al. ZEB1 enhances Warburg effect to facilitate tumorigenesis and metastasis of HCC by transcriptionally activating PFKM. Theranostics 2021; 11: 5926-38.
22.
Prevarskaya N, Skryma R, Shuba Y. Targeting Ca(2)(+) transport in cancer: close reality or long perspective? Expert Opin Ther Targets 2013; 17: 225-41.
23.
Takata T, Tsukuda A, Tsuchiya Y, Akaike T, Watanabe Y. The active-site cysteine residue of Ca2+/calmodulin-dependent protein kinase I is protected from irreversible modification via generation of polysulfidation. Nitric Oxide 2019; 86: 68-75.
24.
Xu H, Yang Y, Deng QW, et al. Governor vessel electro-acupuncture promotes the intrinsic growth ability of spinal neurons through activating calcitonin gene-related peptide/alpha-calcium/calmodulin-dependent protein kinase/neurotrophin-3 pathway after spinal cord injury. J Neurotrauma 2021; 38: 734-45.
25.
Danciu TE, Adam RM, Naruse K, Freeman MR, Hauschka PV. Calcium regulates the PI3K-Akt pathway in stretched osteoblasts. FEBS Lett 2003; 536: 193-7.
26.
Shapovalov G, Lehen’kyi V, Skryma R, Prevarskaya N. TRP channels in cell survival and cell death in normal and transformed cells. Cell Calcium 2011; 50: 295-302.
27.
Liu Y, Wei M, Mao X, Chen T, Lin P, Wang W. Key signaling pathways regulate the development and survival of auditory hair cells. Neural Plast 2021; 2021: 5522717.
28.
Wadgaonkar P, Chen F. Connections between endoplasmic reticulum stress-associated unfolded protein response, mitochondria, and autophagy in arsenic-induced carcinogenesis. Semin Cancer Biol 2021; 76: 258-66.
29.
Heo JH, Seo HN, Choe YJ, et al. T-type Ca2+ channel blockers suppress the growth of human cancer cells. Bioorg Med Chem Lett 2008; 18: 3899-901.
30.
Liu Z, Zhang S, Hou F, Zhang C, Gao J, Wang KW. Inhibition of Ca2+-activated chloride channel ANO1 suppresses ovarian cancer through inactivating PI3K/Akt signaling. Int J Cancer 2019; 144: 2215-26.
31.
Papp B, Brouland JP, Arbabian A, et al. Endoplasmic reticulum calcium pumps and cancer cell differentiation. Biomolecules 2012; 2: 165-86.
32.
Rossi AE, Dirksen RT. Sarcoplasmic reticulum: the dynamic calcium governor of muscle. Muscle Nerve 2006; 33: 715-31.
33.
Wray S, Burdyga T. Sarcoplasmic reticulum function in smooth muscle. Physiol Rev 2010; 90: 113-78.
34.
Zarain-Herzberg A, Izquierdo-Torres E, Hernandez-Oliveras A, Rodriguez G, Lozano-Arriaga D. Sarcoplasmic reticulum Ca(2+) ATPases genes differential expression in breast cancer cells. Gac Med Mex 2021; 157: 343-9.
35.
Flores-Peredo L, Rodriguez G, Zarain-Herzberg A. Induction of cell differentiation activates transcription of the Sarco/Endoplasmic Reticulum calcium-ATPase 3 gene (ATP2A3) in gastric and colon cancer cells. Mol Carcinog 2017; 56: 735-50.
36.
Hewitt DP, Mark PJ, Waddell BJ. Placental expression of peroxisome proliferator-activated receptors in rat pregnancy and the effect of increased glucocorticoid exposure. Biol Reprod 2006; 74: 23-8.
37.
Das BC, Thapa P, Karki R, et al. Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem 2014; 22: 673-83.
38.
Chen YC, Wu JS, Tsai HD, et al. Peroxisome proliferator-activated receptor gamma (PPAR-) and neurodegenerative disorders. Mol Neurobiol 2012; 46: 114-24.
39.
Tian J, Yang L, Wang Z, Yan H. MIR503HG impeded ovarian cancer progression by interacting with SPI1 and preventing TMEFF1 transcription. Aging 2022; 14: 5390-405.
40.
Soares S, Guerreiro SG, Cruz-Martins N, et al. The influence of miRNAs on radiotherapy treatment in prostate cancer – a systematic review. Front Oncol 2021; 11: 704664.
Share
RELATED ARTICLE
| eISSN: | 1896-9151 |
| ISSN: | 1734-1922 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
