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

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
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation

Authors: Yuan-Hua Wu, Wun-Syuan Wu, Li-Ching Lin, Chiang-Shin Liu, Sheng-Yow Ho, Bour-Jr Wang, Bu-Miin Huang, Ya-Ling Yeh, Hui-Wen Chiu, Wei-Lei Yang, Ying-Jan Wang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Oral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. We investigated the role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in OSCC cells treated with bortezomib (a proteasome inhibitor) combined with irradiation (IR) treatment.

Methods

The effects of combined treatment in OSCC cells were investigated using assays of cell viability, autophagy, apoptosis, western blotting, and immunofluorescence staining. The ubiquitination of proteins was analyzed by immunoprecipitation. Stable knockdown of TRAF6 in OSCC cells was constructed with lentivirus. The xenograft murine models were used to observe tumor growth.

Results

We found synergistic effects of bortezomib and IR on the viability of human oral cancer cells. The combination of bortezomib and IR treatment induced autophagic cell death. Furthermore, bortezomib inhibited IR-induced TRAF6 ubiquitination and inhibited TRAF6-mediated Akt activation. Bortezomib reduced TRAF6 protein expression through autophagy-mediated lysosomal degradation. TRAF6 played an oncogenic role in tumorigenesis of human oral cancer cells and oral tumor growth was suppressed by bortezomib and IR treatment. In addition, OSCC patients with expression of TRAF6 showed a trend towards poorer cancer-specific survival when compared with patients without TRAF6 expression.

Conclusions

A combination of a proteasome inhibitor, IR treatment and TRAF6 inhibition could be a novel therapeutic strategy in OSCC.
Appendix
Available only for authorised users
Literature
1.
Petersen PE. Oral cancer prevention and control--the approach of the World Health Organization. Oral Oncol. 2009;45:454–60.CrossRefPubMed
2.
Petruzzi MN, Cherubini K, Salum FG, de Figueiredo MA. Role of tumour-associated macrophages in oral squamous cells carcinoma progression: an update on current knowledge. Diagn Pathol. 2017;12:32.CrossRefPubMedPubMedCentral
3.
Montagnani F, Fornaro L, Frumento P, Vivaldi C, Falcone A, Fioretto L. Multimodality treatment of locally advanced squamous cell carcinoma of the oesophagus: a comprehensive review and network meta-analysis. Crit Rev Oncol Hematol. 2017;114:24–32.CrossRefPubMed
4.
Lo Nigro C, Denaro N, Merlotti A, Merlano M. Head and neck cancer: improving outcomes with a multidisciplinary approach. Cancer Manag Res. 2017;9:363–71.CrossRefPubMedPubMedCentral
5.
Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14:417–33.CrossRefPubMed
6.
Provencio M, Sanchez A. Therapeutic integration of new molecule-targeted therapies with radiotherapy in lung cancer. Transl Lung Cancer Res. 2014;3:89–94.PubMedPubMedCentral
7.
Chiu HW, Lin SW, Lin LC, Hsu YH, Lin YF, Ho SY, Wu YH, Wang YJ. Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6. Cancer Lett. 2015;365:229–39.CrossRefPubMed
8.
Ji CH, Kwon YT. Crosstalk and interplay between the ubiquitin-proteasome system and autophagy. Mol Cells. 2017;40:441–9.PubMedPubMedCentral
9.
Manasanch EE, Korde N, Zingone A, Tageja N, Fernandez de Larrea C, Bhutani M, Wu P, Roschewski M, Landgren O. The proteasome: mechanisms of biology and markers of activity and response to treatment in multiple myeloma. Leuk Lymphoma. 2014;55:1707–14.CrossRefPubMed
10.
Ruschak AM, Slassi M, Kay LE, Schimmer AD. Novel proteasome inhibitors to overcome bortezomib resistance. J Natl Cancer Inst. 2011;103:1007–17.CrossRefPubMed
11.
Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B, Hur L, Grabiner BC, Lin X, Darnay BG, et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science. 2009;325:1134–8.CrossRefPubMedPubMedCentral
12.
He Z, Huang C, Lin G, Ye Y. siRNA-induced TRAF6 knockdown promotes the apoptosis and inhibits the invasion of human lung cancer SPC-A1 cells. Oncol Rep. 2016;35:1933–40.CrossRefPubMedPubMedCentral
13.
Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Dunner K Jr, Huang P, Abbruzzese JL, McConkey DJ. Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer Res. 2005;65:11658–66.CrossRefPubMed
14.
15.
16.
17.
Ohtake F, Tsuchiya H. The emerging complexity of ubiquitin architecture. J Biochem. 2017;161:125–33.PubMed
18.
Fang J, Rhyasen G, Bolanos L, Rasch C, Varney M, Wunderlich M, Goyama S, Jansen G, Cloos J, Rigolino C, et al. Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1. Blood. 2012;120:858–67.CrossRefPubMedPubMedCentral
19.
Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.CrossRef
20.
Chiu HW, Lin JH, Chen YA, Ho SY, Wang YJ. Combination treatment with arsenic trioxide and irradiation enhances cell-killing effects in human fibrosarcoma cells in vitro and in vivo through induction of both autophagy and apoptosis. Autophagy. 2010;6:353–65.CrossRefPubMed
21.
Liu JD, Wang YJ, Chen CH, Yu CF, Chen LC, Lin JK, Liang YC, Lin SY, Ho YS. Molecular mechanisms of G0/G1 cell-cycle arrest and apoptosis induced by terfenadine in human cancer cells. Mol Carcinog. 2003;37:39–50.CrossRefPubMed
22.
Kanzawa T, Kondo Y, Ito H, Kondo S, Germano I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res. 2003;63:2103–8.PubMed
23.
Traganos F, Darzynkiewicz Z. Lysosomal proton pump activity: supravital cell staining with acridine orange differentiates leukocyte subpopulations. Methods Cell Biol. 1994;41:185–94.CrossRefPubMed
24.
Zhang Y, Bai C, Lu D, Wu X, Gao L, Zhang W. Endoplasmic reticulum stress and autophagy participate in apoptosis induced by bortezomib in cervical cancer cells. Biotechnol Lett. 2016;38:357–65.CrossRefPubMed
25.
Kuma A, Matsui M, Mizushima N. LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: caution in the interpretation of LC3 localization. Autophagy. 2007;3:323–8.CrossRefPubMed
26.
Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 2004;11:448–57.CrossRefPubMed
27.
Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y, Yoshimori T. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001;152:657–68.CrossRefPubMedPubMedCentral
28.
Sarkar S, Ravikumar B, Rubinsztein DC. Autophagic clearance of aggregate-prone proteins associated with neurodegeneration. Methods Enzymol. 2009;453:83–110.CrossRefPubMed
29.
Hadian K, Krappmann D. Signals from the nucleus: activation of NF-kappaB by cytosolic ATM in the DNA damage response. Sci Signal. 2011;4:pe2.CrossRefPubMed
30.
Hinz M, Stilmann M, Arslan SC, Khanna KK, Dittmar G, Scheidereit C. A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-kappaB activation. Mol Cell. 2010;40:63–74.CrossRefPubMed
31.
Wu ZH, Wong ET, Shi Y, Niu J, Chen Z, Miyamoto S, Tergaonkar V. ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. Mol Cell. 2010;40:75–86.CrossRefPubMedPubMedCentral
32.
Nedelsky NB, Todd PK, Taylor JP. Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim Biophys Acta. 2008;1782:691–9.CrossRefPubMedPubMedCentral
33.
Xin Y, Jiang F, Yang C, Yan Q, Guo W, Huang Q, Zhang L, Jiang G. Role of autophagy in regulating the radiosensitivity of tumor cells. J Cancer Res Clin Oncol. 2017;143:2147–57.CrossRefPubMed
34.
35.
Shen HM, Codogno P. Autophagic cell death: loch ness monster or endangered species? Autophagy. 2011;7:457–65.CrossRefPubMed
36.
Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 2009;452:181–97.CrossRefPubMed
37.
Colosetti P, Puissant A, Robert G, Luciano F, Jacquel A, Gounon P, Cassuto JP, Auberger P. Autophagy is an important event for megakaryocytic differentiation of the chronic myelogenous leukemia K562 cell line. Autophagy. 2009;5:1092–8.CrossRefPubMed
38.
Chiu HW, Chen YA, Ho SY, Wang YJ. Arsenic trioxide enhances the radiation sensitivity of androgen-dependent and -independent human prostate cancer cells. PLoS One. 2012;7:e31579.CrossRefPubMedPubMedCentral
39.
Sartore-Bianchi A, Gasparri F, Galvani A, Nici L, Darnowski JW, Barbone D, Fennell DA, Gaudino G, Porta C, Mutti L. Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma. Clin Cancer Res. 2007;13:5942–51.CrossRefPubMed
40.
Busacca S, Chacko AD, Klabatsa A, Arthur K, Sheaff M, Barbone D, Mutti L, Gunasekharan VK, Gorski JJ, El-Tanani M, et al. BAK and NOXA are critical determinants of mitochondrial apoptosis induced by bortezomib in mesothelioma. PLoS One. 2013;8:e65489.CrossRefPubMedPubMedCentral
41.
42.
Deng Z, Purtell K, Lachance V, Wold MS, Chen S, Yue Z. Autophagy receptors and neurodegenerative diseases. Trends Cell Biol. 2017;27:491–504.CrossRefPubMed
43.
Yao F, Han Q, Zhong C, Zhao H. TRAF6 promoted the tumorigenicity of esophageal squamous cell carcinoma. Tumour Biol. 2013;34:3201–7.CrossRefPubMed
44.
Han Q, Yao F, Zhong C, Zhao H. TRAF6 promoted the metastasis of esophageal squamous cell carcinoma. Tumour Biol. 2014;35:715–21.CrossRefPubMed
45.
Zhang T, Wang H, Han L. Expression and clinical significance of tumor necrosis factor receptor-associated factor 6 in patients with Colon Cancer. Iran Red Crescent Med J. 2016;18:e23931.PubMedPubMedCentral
Metadata
Title
Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation
Authors
Yuan-Hua Wu
Wun-Syuan Wu
Li-Ching Lin
Chiang-Shin Liu
Sheng-Yow Ho
Bour-Jr Wang
Bu-Miin Huang
Ya-Ling Yeh
Hui-Wen Chiu
Wei-Lei Yang
Ying-Jan Wang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0760-0

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Research

Exosomal TRIM3 is a novel marker and therapy target for gastric cancer

Review

Advances in circular RNAs and their roles in breast Cancer

Research

Notch1 signaling in melanoma cells promoted tumor-induced immunosuppression via upregulation of TGF-β1

Research

TFAP2C promotes stemness and chemotherapeutic resistance in colorectal cancer via inactivating hippo signaling pathway

Research

Long non-coding RNA UBE2CP3 enhances HCC cell secretion of VEGFA and promotes angiogenesis by activating ERK1/2/HIF-1α/VEGFA signalling in hepatocellular carcinoma

Research

Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models
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