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
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Tumor necrosis factor-α attenuates starvation-induced apoptosis through upregulation of ferritin heavy chain in hepatocellular carcinoma cells

Authors: Xingrui Kou, Yingying Jing, Weijie Deng, Kai Sun, Zhipeng Han, Fei Ye, Guofeng Yu, Qingmin Fan, Lu Gao, Qiudong Zhao, Xue Zhao, Rong Li, Lixin Wei, Mengchao Wu

Published in: BMC Cancer | Issue 1/2013

Login to get access

Abstract

Background

Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. TNF-α, which is an extraordinarily pleiotropic cytokine, could be an endogenous tumor promoter in some tumor types. The basic objective of this study was to investigate the effects of TNF-α on the cell viability and apoptosis of hepatocellular carcinoma cells under serum starvation, and to identify the molecular mechanisms involved.

Methods

For this purpose, five different concentrations of TNF-α and two different serum settings (serum-cultured and serum-deprived) were used to investigate the effects of TNF-α on the cell viability and apoptosis of Hep3B and SMMC-7721 cells.

Results

TNF-α (10 ng/ml) attenuated serum starvation-induced apoptosis of hepatocellular carcinoma cells, and autophagy conferred this process. BAY11-7082, a specific inhibitor of NF-κB, reversed the suppression of serum starvation-induced apoptosis by TNF-α. Moreover, TNF-α-induced NF-κB transactivation was suppressed by autophagy inhibitor 3-MA. In addition, TNF-α up-regulated Ferritin heavy chain (FHC) transiently by NF-κB activation and FHC levels were correlated with the TNF-α-induced protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells. Furthermore, FHC-mediated inhibition of apoptosis depended on suppressing ROS accumulation.

Conclusions

Our findings suggested that autophagy conferred the TNF-α protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells, the mechanism involved with the activation of the TNF-α/ NF-κB /FHC signaling pathway.
Appendix
Available only for authorised users
Literature
1.
Egberts JH, Cloosters V, Noack A, Schniewind B, Thon L, Klose S, et al: Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 2008, 68: 1443-1450. 10.1158/0008-5472.CAN-07-5704.CrossRefPubMed
2.
Luo JL, Maeda S, Hsu LC, Yagita H, Karin M: Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNF-alpha to TRAIL-mediated tumor regression. Cancer Cell. 2004, 6: 297-305. 10.1016/j.ccr.2004.08.012.CrossRefPubMed
3.
Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, et al: Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985, 228: 149-154. 10.1126/science.3856324.CrossRefPubMed
4.
van Horssen R, Ten Hagen TL, Eggermont AM: TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility. Oncologist. 2006, 11: 397-408. 10.1634/theoncologist.11-4-397.CrossRefPubMed
5.
Benedetti G, Fredriksson L, Herpers B, Meerman J, van de Water B, de Graauw M: TNF-alpha-mediated NF-kappaB survival signaling impairment by cisplatin enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells. Biochem Pharmacol. 2013, 85: 274-286. 10.1016/j.bcp.2012.10.012.CrossRefPubMed
6.
Lovas A, Weidemann A, Albrecht D, Wiechert L, Weih D, Weih F: p100 Deficiency is insufficient for full activation of the alternative NF-kappaB pathway: TNF cooperates with p52-RelB in target gene transcription. PLoS One. 2012, 7: e42741-10.1371/journal.pone.0042741.CrossRefPubMedPubMedCentral
7.
Baeuerle PA, Baltimore D: NF-kappa B: ten years after. Cell. 1996, 87: 13-20. 10.1016/S0092-8674(00)81318-5.CrossRefPubMed
8.
Mayo MW, Baldwin AS: The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta. 2000, 1470: M55-M62.PubMed
9.
Liu ZG, Hsu H, Goeddel DV, Karin M: Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell. 1996, 87: 565-576. 10.1016/S0092-8674(00)81375-6.CrossRefPubMed
10.
Zhang J, Cado D, Chen A, Kabra NH, Winoto A: Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature. 1998, 392: 296-300. 10.1038/32681.CrossRefPubMed
11.
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS: NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998, 281: 1680-1683.CrossRefPubMed
12.
Roperto S, Borzacchiello G, Brun R, Costanzo F, Faniello MC, Raso C, et al: Ferritin heavy chain (FHC) is Up-regulated in papillomavirus-associated urothelial tumours of the urinary bladder in cattle. J Comp Pathol. 2010, 142: 9-18. 10.1016/j.jcpa.2009.05.009.CrossRefPubMed
13.
Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G: NF-kappaB and JNK: an intricate affair. Cell Cycle. 2004, 3: 1524-1529. 10.4161/cc.3.12.1321.CrossRefPubMed
14.
Jing YY, Han ZP, Sun K, Zhang SS, Hou J, Liu Y, et al: Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 2012, 10: 98-10.1186/1741-7015-10-98.CrossRefPubMedPubMedCentral
15.
Qin Y, Camoretti-Mercado B, Blokh L, Long CG, Ko FD, Hamann KJ: Fas resistance of leukemic eosinophils is due to activation of NF-κB by Fas ligation. J Immunol. 2002, 169: 3536-3544.CrossRefPubMed
16.
Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P: The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity. 1998, 8: 297-303. 10.1016/S1074-7613(00)80535-X.CrossRefPubMed
17.
Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A, et al: Early lethality, functional NF-κB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity. 1997, 7: 715-725. 10.1016/S1074-7613(00)80391-X.CrossRefPubMed
18.
Colleran A, Ryan A, O’Gorman A, Mureau C, Liptrot C, Dockery P, et al: Autophagosomal IkappaB alpha degradation plays a role in the long term control of tumor necrosis factor-alpha-induced nuclear factor-kappaB (NF-kappaB) activity. J Biol Chem. 2011, 286: 22886-22893. 10.1074/jbc.M110.199950.CrossRefPubMedPubMedCentral
19.
Notarbartolo M, Poma P, Perri D, Dusonchet L, Cervello M, D’Alessandro N: Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression. Cancer Lett. 2005, 224: 53-65. 10.1016/j.canlet.2004.10.051.CrossRefPubMed
20.
You M, Ku PT, Hrdlicková R, Bose HR: ch-IAP1, a member of the inhibitor-of-apoptosis protein family, is a mediator of the antiapoptotic activity of the v-Rel oncoprotein. Mol Cell Biol. 1997, 17: 7328-7341.CrossRefPubMedPubMedCentral
21.
Catz SD, Johnson JL: Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene. 2001, 20: 7342-7351. 10.1038/sj.onc.1204926.CrossRefPubMed
22.
Hao XS, Hao JH, Liu FT, Newland AC, Jia L: Potential mechanisms of leukemia cell resistance to TRAIL-induced apopotosis. Apoptosis. 2003, 8: 601-607.CrossRefPubMed
23.
LaCasse EC, Baird S, Korneluk RG, MacKenzie AE: The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene. 1998, 17: 3247-3259.CrossRefPubMed
24.
Mattson MP, Meffert MK: Roles for NF-κB in nerve cell survival, plasticity, and disease. Cell Death & Differentiation. 2006, 13: 852-860. 10.1038/sj.cdd.4401837.CrossRef
25.
Schwenzer R, Siemienski K, Liptay S, Schubert G, Peters N, Scheurich P, et al: The human tumor necrosis factor (TNF) receptor-associated factor 1 gene (TRAF1) is up-regulated by cytokines of the TNF ligand family and modulates TNF-induced activation of NF-κB and c-Jun N-terminal kinase. J Biol Chem. 1999, 274: 19368-19374. 10.1074/jbc.274.27.19368.CrossRefPubMed
26.
Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K: Ferritin heavy chain upregulation by NF-κB inhibits TNFα-induced apoptosis by suppressing reactive oxygen species. Cell. 2004, 119: 529-542. 10.1016/j.cell.2004.10.017.CrossRefPubMed
27.
Ding WX, Yin XM: Dissection of the multiple mechanisms of TNF-α-induced apoptosis in liver injury. J Cell Mol Med. 2004, 8: 445-454. 10.1111/j.1582-4934.2004.tb00469.x.CrossRefPubMed
28.
29.
Bertazza L, Mocellin S: The dual role of tumor necrosis factor (TNF) in cancer biology. Curr Med Chem. 2010, 17: 3337-3352. 10.2174/092986710793176339.CrossRefPubMed
30.
Liu RY, Fan C, Liu G, Olashaw NE, Zuckerman KS: Activation of p38 mitogen-activated protein kinase is required for tumor necrosis factor-alpha -supported proliferation of leukemia and lymphoma cell lines. J Biol Chem. 2000, 275: 21086-21093. 10.1074/jbc.M001281200.CrossRefPubMed
31.
Katerinaki E, Evans GS, Lorigan PC, MacNeil S: TNF-alpha increases human melanoma cell invasion and migration in vitro: the role of proteolytic enzymes. Br J Cancer. 2003, 89: 1123-1129. 10.1038/sj.bjc.6601257.CrossRefPubMedPubMedCentral
32.
Nabors LB, Suswam E, Huang Y, Yang X, Johnson MJ, King PH: Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR. Cancer Res. 2003, 63: 4181-4187.PubMed
33.
Knight B, Yeoh GC, Husk KL, Ly T, Abraham LJ, Yu C, et al: Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J Exp Med. 2000, 192: 1809-1818. 10.1084/jem.192.12.1809.CrossRefPubMedPubMedCentral
34.
Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al: NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004, 431: 461-466. 10.1038/nature02924.CrossRefPubMed
35.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al: Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006, 10: 51-64. 10.1016/j.ccr.2006.06.001.CrossRefPubMedPubMedCentral
36.
37.
38.
Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, et al: Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ. 2008, 16: 87-93.CrossRefPubMed
39.
Comb WC, Cogswell P, Sitcheran R, Baldwin AS: IKK-dependent, NF-kappaB-independent control of autophagic gene expression. Oncogene. 2011, 30: 1727-1732. 10.1038/onc.2010.553.CrossRefPubMed
40.
Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E, Vitale I, et al: The IKK complex contributes to the induction of autophagy. EMBO J. 2010, 29: 619-631. 10.1038/emboj.2009.364.CrossRefPubMed
41.
Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G: The NF-kappaB-mediated control of ROS and JNK signaling. Histol Histopathol. 2006, 21: 69-80.PubMed
42.
Torti FM, Torti SV: Regulation of ferritin genes and protein. Blood. 2002, 99: 3505-3516. 10.1182/blood.V99.10.3505.CrossRefPubMed
43.
Aung W, Hasegawa S, Furukawa T, Saga T: Potential role of ferritin heavy chain in oxidative stress and apoptosis in human mesothelial and mesothelioma cells: implications for asbestos-induced oncogenesis. Carcinogenesis. 2007, 28: 2047-2052. 10.1093/carcin/bgm090.CrossRefPubMed
Metadata
Title
Tumor necrosis factor-α attenuates starvation-induced apoptosis through upregulation of ferritin heavy chain in hepatocellular carcinoma cells
Authors
Xingrui Kou
Yingying Jing
Weijie Deng
Kai Sun
Zhipeng Han
Fei Ye
Guofeng Yu
Qingmin Fan
Lu Gao
Qiudong Zhao
Xue Zhao
Rong Li
Lixin Wei
Mengchao Wu
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-438

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue

Research article

Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer - overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression

Research article

Classification tree analysis to enhance targeting for follow-up exam of colorectal cancer screening

Technical advance

Quantitative threefold allele-specific PCR (QuanTAS-PCR) for highly sensitive JAK2V617F mutant allele detection

Research article

A pri-miR-218variant and risk of cervical carcinoma in Chinese women

Research article

High expression of ezrin predicts poor prognosis in uterine cervical cancer

Research article

Evaluating human cancer cell metastasis in zebrafish
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