Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival

Authors: Juan M Funes, Stephen Henderson, Rachel Kaufman, James M Flanagan, Mathew Robson, Barbara Pedley, Salvador Moncada, Chris Boshoff

Published in: Molecular Cancer | Issue 1/2014

Login to get access

Abstract

Background

The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious.

Methods

We employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 (n = 6 mice per group). Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two-sided.

Results

We found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS/RAF/ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1α destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma (P = 0.0341), kidney (P = 0.0203) and prostate (P = 0.00279) cancers.

Conclusions

Our data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tumor growth.
Appendix
Available only for authorised users
Literature
1.
Szatrowski TP, Nathan CF: Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991, 51: 794-798.PubMed
2.
Pelicano H, Carney D, Huang P: ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 2004, 7: 97-110. 10.1016/j.drup.2004.01.004CrossRefPubMed
3.
4.
Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I: An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997, 236: 313-322. 10.1006/bbrc.1997.6943CrossRefPubMed
5.
Venugopal R, Jaiswal AK: Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci USA. 1996, 93: 14960-14965. 10.1073/pnas.93.25.14960PubMedCentralCrossRefPubMed
6.
McMahon M, Itoh K, Yamamoto M, Hayes JD: Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003, 278: 21592-21600. 10.1074/jbc.M300931200CrossRefPubMed
7.
Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M: Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999, 13: 76-86. 10.1101/gad.13.1.76PubMedCentralCrossRefPubMed
8.
Zhang DD: Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006, 38: 769-789. 10.1080/03602530600971974CrossRefPubMed
9.
Itoh K, Mimura J, Yamamoto M: Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal. 2010, 13: 1665-1678. 10.1089/ars.2010.3222CrossRefPubMed
10.
Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL: Nrf2, a Cap'n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem. 1999, 274: 26071-26078. 10.1074/jbc.274.37.26071CrossRefPubMed
11.
Wild AC, Moinova HR, Mulcahy RT: Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem. 1999, 274: 33627-33636. 10.1074/jbc.274.47.33627CrossRefPubMed
12.
McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C, Hayes JD: The Cap'n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res. 2001, 61: 3299-3307.PubMed
13.
Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, Motohashi H: Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012, 22: 66-79. 10.1016/j.ccr.2012.05.016CrossRefPubMed
14.
Zhang Y, Gordon GB: A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway. Mol Cancer Ther. 2004, 3: 885-893.PubMed
15.
16.
Nair S, Li W, Kong AN: Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells. Acta Pharmacol Sin. 2007, 28: 459-472. 10.1111/j.1745-7254.2007.00549.xCrossRefPubMed
17.
Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW: Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA. 2001, 98: 3410-3415. 10.1073/pnas.051618798PubMedCentralCrossRefPubMed
18.
Iida K, Itoh K, Kumagai Y, Oyasu R, Hattori K, Kawai K, Shimazui T, Akaza H, Yamamoto M: Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res. 2004, 64: 6424-6431. 10.1158/0008-5472.CAN-04-1906CrossRefPubMed
19.
Aoki Y, Hashimoto AH, Amanuma K, Matsumoto M, Hiyoshi K, Takano H, Masumura K, Itoh K, Nohmi T, Yamamoto M: Enhanced spontaneous and benzo(a)pyrene-induced mutations in the lung of Nrf2-deficient gpt delta mice. Cancer Res. 2007, 67: 5643-5648. 10.1158/0008-5472.CAN-06-3355CrossRefPubMed
20.
Kitamura Y, Umemura T, Kanki K, Kodama Y, Kitamoto S, Saito K, Itoh K, Yamamoto M, Masegi T, Nishikawa A, Hirose M: Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo[4, 5-f]quinoline. Cancer Sci. 2007, 98: 19-24. 10.1111/j.1349-7006.2006.00352.xCrossRefPubMed
21.
Satoh H, Moriguchi T, Taguchi K, Takai J, Maher JM, Suzuki T, Winnard PT, Raman V, Ebina M, Nukiwa T, Yamamoto M: Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis. 2010, 31: 1833-1843. 10.1093/carcin/bgq105CrossRefPubMed
22.
23.
24.
Hayes JD, McMahon M: NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci. 2009, 34: 176-188. 10.1016/j.tibs.2008.12.008CrossRefPubMed
25.
DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES: Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011, 475: 106-109. 10.1038/nature10189PubMedCentralCrossRefPubMed
26.
The Cancer Genome Atlas Research Network: Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012, 489: 519-525. 10.1038/nature11404PubMedCentralCrossRef
27.
Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang MI, Kobayashi A, Yokoyama S, Yamamoto M: Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006, 21: 689-700. 10.1016/j.molcel.2006.01.013CrossRefPubMed
28.
Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E: Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006, 3: e420- 10.1371/journal.pmed.0030420PubMedCentralCrossRefPubMed
29.
Nioi P, Nguyen T: A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun. 2007, 362: 816-821. 10.1016/j.bbrc.2007.08.051CrossRefPubMed
30.
Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S: Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA. 2008, 105: 13568-13573. 10.1073/pnas.0806268105PubMedCentralCrossRefPubMed
31.
Funes JM, Quintero M, Henderson S, Martinez D, Qureshi U, Westwood C, Clements MO, Bourboulia D, Pedley RB, Moncada S, Boshoff C: Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production. Proc Natl Acad Sci USA. 2007, 104: 6223-6228. 10.1073/pnas.0700690104PubMedCentralCrossRefPubMed
32.
Rangarajan A, Hong SJ, Gifford A, Weinberg RA: Species- and cell type-specific requirements for cellular transformation. Cancer Cell. 2004, 6: 171-183. 10.1016/j.ccr.2004.07.009CrossRefPubMed
33.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005, 102: 15545-15550. 10.1073/pnas.0506580102PubMedCentralCrossRefPubMed
34.
Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009, 458: 780-783. 10.1038/nature07733PubMedCentralCrossRefPubMed
35.
Wang X, Tomso DJ, Chorley BN, Cho HY, Cheung VG, Kleeberger SR, Bell DA: Identification of polymorphic antioxidant response elements in the human genome. Hum Mol Genet. 2007, 16: 1188-1200. 10.1093/hmg/ddm066PubMedCentralCrossRefPubMed
36.
Loignon M, Miao W, Hu L, Bier A, Bismar TA, Scrivens PJ, Mann K, Basik M, Bouchard A, Fiset PO: Cul3 overexpression depletes Nrf2 in breast cancer and is associated with sensitivity to carcinogens, to oxidative stress, and to chemotherapy. Mol Cancer Ther. 2009, 8: 2432-2440. 10.1158/1535-7163.MCT-08-1186CrossRefPubMed
37.
Thangasamy A, Rogge J, Krishnegowda NK, Freeman JW, Ammanamanchi S: Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion. J Biol Chem. 2011, 286: 32115-32122. 10.1074/jbc.M111.245746PubMedCentralCrossRefPubMed
38.
Nguyen T, Sherratt PJ, Huang HC, Yang CS, Pickett CB: Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem. 2003, 278: 4536-4541. 10.1074/jbc.M207293200CrossRefPubMed
39.
Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J: Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci. 2005, 83: 313-328.CrossRefPubMed
40.
Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT: Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem. 2000, 275: 25130-25138. 10.1074/jbc.M001914200CrossRefPubMed
41.
42.
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM: ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004, 6: 1-6.PubMedCentralCrossRefPubMed
43.
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B: Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010, 18: 11-22. 10.1016/j.ccr.2010.05.026PubMedCentralCrossRefPubMed
44.
Geiszt M, Leto TL: The Nox family of NAD(P)H oxidases: host defense and beyond. J Biol Chem. 2004, 279: 51715-51718. 10.1074/jbc.R400024200CrossRefPubMed
45.
Tan Y, Ichikawa T, Li J, Si Q, Yang H, Chen X, Goldblatt CS, Meyer CJ, Li X, Cai L, Cui T: Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes. 2011, 60: 625-633. 10.2337/db10-1164PubMedCentralCrossRefPubMed
46.
Yaari-Stark S, Shaked M, Nevo-Caspi Y, Jacob-Hircsh J, Shamir R, Rechavi G, Kloog Y: Ras inhibits endoplasmic reticulum stress in human cancer cells with amplified Myc. Int J Cancer. 2010, 126: 2268-2281.PubMed
47.
Vasseur S, Malicet C, Calvo EL, Labrie C, Berthezene P, Dagorn JC, Iovanna JL: Gene expression profiling by DNA microarray analysis in mouse embryonic fibroblasts transformed by rasV12 mutated protein and the E1A oncogene. Mol Cancer. 2003, 2: 19- 10.1186/1476-4598-2-19PubMedCentralCrossRefPubMed
48.
Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M: Tumour biology: senescence in premalignant tumours. Nature. 2005, 436: 642- 10.1038/436642aCrossRefPubMed
49.
Niture SK, Jaiswal AK: Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem. 2012, 287: 9873-9886. 10.1074/jbc.M111.312694PubMedCentralCrossRefPubMed
50.
Niture SK, Jaiswal AK: Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med. 2012, 57C: 119-131.
51.
Chinery R, Brockman JA, Peeler MO, Shyr Y, Beauchamp RD, Coffey RJ: Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta. Nat Med. 1997, 3: 1233-1241. 10.1038/nm1197-1233CrossRefPubMed
52.
Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH: Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 2007, 67: 10823-10830. 10.1158/0008-5472.CAN-07-0783CrossRefPubMed
53.
Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Lee YM, Ku SK, Jung Y, Kwak MK: NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Cancer Res. 2011, 71: 2260-2275. 10.1158/0008-5472.CAN-10-3007CrossRefPubMed
54.
Sporn MB, Liby KT: NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012, 12: 564-571. 10.1038/nrc3278CrossRefPubMed
55.
Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M: Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 2013, 73: 4158-4168. 10.1158/0008-5472.CAN-12-4499CrossRefPubMed
Metadata
Title
Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival
Authors
Juan M Funes
Stephen Henderson
Rachel Kaufman
James M Flanagan
Mathew Robson
Barbara Pedley
Salvador Moncada
Chris Boshoff
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-20

Other articles of this Issue 1/2014

Molecular Cancer 1/2014 Go to the issue

Research

CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to Erlotinib via transcriptional regulation of EGFR

Research

TFAP2B overexpression contributes to tumor growth and a poor prognosis of human lung adenocarcinoma through modulation of ERK and VEGF/PEDF signaling

Research

Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer

Short communication

Direct but not indirect co-culture with osteogenically differentiated human bone marrow stromal cells increases RANKL/OPG ratio in human breast cancer cells generating bone metastases

Research

Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway

Research

Agonist activation of estrogen receptor beta (ERβ) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits