Restoration of Type 1 Iodothyronine Deiodinase Expression in Renal Cancer Cells Downregulates Oncoproteins and Affects Key Metabolic Pathways As Well As Anti-oxidative System

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2017 Dec 23

PMID 29272308

Citations 12

Authors

Piotr Poplawski

Jacek R Wisniewski

Eddy Rijntjes

Keith Richards

Beata Rybicka

Josef Kohrle

Agnieszka Piekielko-Witkowska

Affiliations

Soon will be listed here.

Abstract

Type 1 iodothyronine deiodinase (DIO1) contributes to deiodination of 3,5,3',5'-tetraiodo-L-thyronine (thyroxine, T4) yielding of 3,5,3'-triiodothyronine (T3), a powerful regulator of cell differentiation, proliferation, and metabolism. Our previous work showed that loss of DIO1 enhances proliferation and migration of renal cancer cells. However, the global effects of DIO1 expression in various tissues affected by cancer remain unknown. Here, the effects of stable DIO1 re-expression were analyzed on the proteome of renal cancer cells, followed by quantitative real-time PCR validation in two renal cancer-derived cell lines. DIO1-induced changes in intracellular concentrations of thyroid hormones were quantified by L-MS/MS and correlations between expression of DIO1 and potential target genes were determined in tissue samples from renal cancer patients. Stable re-expression of DIO1, resulted in 26 downregulated proteins while 59 proteins were overexpressed in renal cancer cells. The 'downregulated' group consisted mainly of oncoproteins (e.g. STAT3, ANPEP, TGFBI, TGM2) that promote proliferation, migration and invasion. Furthermore, DIO1 re-expression enhanced concentrations of two subunits of thyroid hormone transporter (SLC7A5, SLC3A2), enzymes of key pathways of cellular energy metabolism (e.g. TKT, NAMPT, IDH2), sex steroid metabolism and anti-oxidative response (AKR1C2, AKR1B10). DIO1 expression resulted in elevated intracellular concentration of T4. Expression of DIO1-affected genes strongly correlated with DIO1 transcript levels in tissue samples from renal cancer patients as well as with their poor survival. This first study addressing effects of deiodinase re-expression on proteome of cancer cells demonstrates that induced DIO1 re-expression in renal cancer robustly downregulates oncoproteins, affects key metabolic pathways, and triggers proteins involved in anti-oxidative protection. This data supports the notion that suppressed DIO1 expression and changes in local availability of thyroid hormones might favor a shift from a differentiated to a more proliferation-prone state of cancer tissues and cell lines.

Citing Articles

The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer.

Alfandari A, Moskovich D, Weisz A, Katzav A, Kidron D, Beiner M Mol Oncol. 2024; 18(9):2298-2313.

PMID: 38429887 PMC: 11467794. DOI: 10.1002/1878-0261.13612.

Association of clinicopathologic and molecular factors with the occurrence of positive margins in breast cancer.

Praveen Kumar A, Vicente D, Liu J, Raj-Kumar P, Deyarmin B, Lin X Breast Cancer Res Treat. 2023; 204(1):15-26.

PMID: 38038766 PMC: 10805852. DOI: 10.1007/s10549-023-07157-x.

Ferroptosis and its emerging role in esophageal cancer.

Maimaitizunong R, Wang K, Li H Front Mol Biosci. 2022; 9:1027912.

PMID: 36237575 PMC: 9551460. DOI: 10.3389/fmolb.2022.1027912.

Deiodinases and Cancer.

Nappi A, De Stefano M, Dentice M, Salvatore D Endocrinology. 2021; 162(4).

PMID: 33539515 PMC: 7906444. DOI: 10.1210/endocr/bqab016.

8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a Cause of Autoimmune Thyroid Diseases (AITD) During Pregnancy?.

Halczuk K, Boguszewska K, Urbaniak S, Szewczuk M, Karwowski B Yale J Biol Med. 2020; 93(4):501-515.

PMID: 33005115 PMC: 7513436.

References

Dentice M, Luongo C, Huang S, Ambrosio R, Elefante A, Mirebeau-Prunier D . Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proc Natl Acad Sci U S A. 2007; 104(36):14466-71. PMC: 1964817. DOI: 10.1073/pnas.0706754104. View

Wisniewski J . Label-Free and Standard-Free Absolute Quantitative Proteomics Using the "Total Protein" and "Proteomic Ruler" Approaches. Methods Enzymol. 2017; 585:49-60. DOI: 10.1016/bs.mie.2016.10.002. View

Johnston P, Grandis J . STAT3 signaling: anticancer strategies and challenges. Mol Interv. 2011; 11(1):18-26. PMC: 3063716. DOI: 10.1124/mi.11.1.4. View

Moeller L, Fuhrer D . Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer. 2013; 20(2):R19-29. DOI: 10.1530/ERC-12-0219. View

Richards K, Schanze N, Monk R, Rijntjes E, Rathmann D, Kohrle J . A validated LC-MS/MS method for cellular thyroid hormone metabolism: Uptake and turnover of mono-iodinated thyroid hormone metabolites by PCCL3 thyrocytes. PLoS One. 2017; 12(8):e0183482. PMC: 5570372. DOI: 10.1371/journal.pone.0183482. View

Baldewijns M, van Vlodrop I, Vermeulen P, Soetekouw P, van Engeland M, de Bruine A . VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010; 221(2):125-38. DOI: 10.1002/path.2689. View

Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M . EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015; 67(5):913-24. DOI: 10.1016/j.eururo.2015.01.005. View

Shang D, Liu Y, Yang P, Chen Y, Tian Y . TGFBI-promoted adhesion, migration and invasion of human renal cell carcinoma depends on inactivation of von Hippel-Lindau tumor suppressor. Urology. 2012; 79(4):966.e1-7. DOI: 10.1016/j.urology.2011.12.011. View

Szklarczyk D, Morris J, Cook H, Kuhn M, Wyder S, Simonovic M . The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2016; 45(D1):D362-D368. PMC: 5210637. DOI: 10.1093/nar/gkw937. View

10.

Wang Z, Zheng H, Gao W, Han J, Cao J, Yang Y . eIF5B increases ASAP1 expression to promote HCC proliferation and invasion. Oncotarget. 2016; 7(38):62327-62339. PMC: 5308730. DOI: 10.18632/oncotarget.11469. View

11.

Guo A, Arbab A, Falck J, Chen P, Edwards P, Roman R . Activation of vascular endothelial growth factor through reactive oxygen species mediates 20-hydroxyeicosatetraenoic acid-induced endothelial cell proliferation. J Pharmacol Exp Ther. 2007; 321(1):18-27. DOI: 10.1124/jpet.106.115360. View

12.

Ambrosio R, De Stefano M, Di Girolamo D, Salvatore D . Thyroid hormone signaling and deiodinase actions in muscle stem/progenitor cells. Mol Cell Endocrinol. 2017; 459:79-83. DOI: 10.1016/j.mce.2017.06.014. View

13.

Tun H, Marlow L, von Roemeling C, Cooper S, Kreinest P, Wu K . Pathway signature and cellular differentiation in clear cell renal cell carcinoma. PLoS One. 2010; 5(5):e10696. PMC: 2872663. DOI: 10.1371/journal.pone.0010696. View

14.

Kalthoff S, Ehmer U, Freiberg N, Manns M, Strassburg C . Interaction between oxidative stress sensor Nrf2 and xenobiotic-activated aryl hydrocarbon receptor in the regulation of the human phase II detoxifying UDP-glucuronosyltransferase 1A10. J Biol Chem. 2010; 285(9):5993-6002. PMC: 2825393. DOI: 10.1074/jbc.M109.075770. View

15.

Poplawski P, Tohge T, Boguslawska J, Rybicka B, Tanski Z, Trevino V . Integrated transcriptomic and metabolomic analysis shows that disturbances in metabolism of tumor cells contribute to poor survival of RCC patients. Biochim Biophys Acta Mol Basis Dis. 2016; 1863(3):744-752. DOI: 10.1016/j.bbadis.2016.12.011. View

16.

Ducker C, Upson J, French K, Smith C . Two N-myristoyltransferase isozymes play unique roles in protein myristoylation, proliferation, and apoptosis. Mol Cancer Res. 2005; 3(8):463-76. PMC: 2908404. DOI: 10.1158/1541-7786.MCR-05-0037. View

17.

Hidaka H, Seki N, Yoshino H, Yamasaki T, Yamada Y, Nohata N . Tumor suppressive microRNA-1285 regulates novel molecular targets: aberrant expression and functional significance in renal cell carcinoma. Oncotarget. 2012; 3(1):44-57. PMC: 3292891. DOI: 10.18632/oncotarget.417. View

18.

Abu Aboud O, Chen C, Senapedis W, Baloglu E, Argueta C, Weiss R . Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth. Mol Cancer Ther. 2016; 15(9):2119-29. PMC: 5010932. DOI: 10.1158/1535-7163.MCT-16-0197. View

19.

Pachucki J, Ambroziak M, Tanski Z, Luczak J, Nauman J, Nauman A . Type I 5'-iodothyronine deiodinase activity and mRNA are remarkably reduced in renal clear cell carcinoma. J Endocrinol Invest. 2001; 24(4):253-61. DOI: 10.1007/BF03343855. View

20.

Tomczak K, Czerwinska P, Wiznerowicz M . The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn). 2015; 19(1A):A68-77. PMC: 4322527. DOI: 10.5114/wo.2014.47136. View