The Association of Neuronal Stress with Activating Transcription Factor 3 in Dorsal Root Ganglion of in vivo and in vitro Models of Bortezomib- Induced Neuropathy

Author(s): Yiting Yin, Xin Qi, Yuan Qiao, Huaxiang Liu, Zihan Yan, Hao Li, Zhen Liu*

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 1 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: The notion that proteasome inhibitor bortezomib (BTZ) induced intracellular oxidative stress resulting in peripheral neuropathy has been generally accepted. The association of mitochondrial dysfunction, cell apoptosis, and endoplasmic reticulum (ER) stress with intracellular oxidative stress is ambiguous and still needs to be investigated. The activation of activating transcription factor 3 (ATF3) is a stress-hub gene which was upregulated in dorsal root ganglion (DRG) neurons after different kinds of peripheral nerve injuries.

Objective: To investigate a mechanism underlying the action of BTZ-induced intracellular oxidative stress, mitochondrial dysfunction, cell apoptosis, and ER stress via activation of ATF3.

Methods: Primary cultured DRG neurons with BTZ induced neurotoxicity and DRG from BTZ induced painful peripheral neuropathic rats were used to approach these questions.

Results: BTZ administration caused the upregulation of ATF3 paralleled with intracellular oxidative stress, mitochondrial dysfunction, cell apoptosis, and ER stress in DRG neurons both in vitro and in vivo. Blocking ATF3 signaling by small interfering RNA (siRNA) gene silencing technology resulted in decreased intracellular oxidative stress, mitochondrial dysfunction, cell apoptosis, and ER stress in DRG neurons after BTZ treatment.

Conclusion: This study exhibited important mechanistic insight into how BTZ induces neurotoxicity through the activation of ATF3 resulting in intracellular oxidative stress, mitochondrial dysfunction, cell apoptosis, and ER stress and provided a novel potential therapeutic target by blocking ATF3 signaling.

Keywords: Oxidative stress, mitochondrial dysfunction, cell apoptosis, endoplasmic reticulum stress, activating transcription factor 3, bortezomib, neuropathy, dorsal root ganglion.

Liapis, K.; Kastritis, E.; Bagratouni, T.; Vassiliou, S.; Papachristidis, A.; Charitaki, E.; Alevizopoulos, N.; Harhalakis, N.; Terpos, E.; Delimpasi, S.; Dimopoulos, M.A. Early tumor-cell gene expression changes may predict the response to first-line bortezomib-based therapy in patients with newly diagnosed multiple myeloma. J. BUON, 2015, 20(5), 1314-1321.
Mohan, M.; Matin, A.; Davies, F.E. Update on the optimal use of bortezomib in the treatment of multiple myeloma. Cancer Manag. Res., 2017, 9, 51-63.
Dou, Q.P.; Zonder, J.A. Overview of proteasome inhibitor-based anti-cancer therapies: perspective on bortezomib and second generation proteasome inhibitors versus future generation inhibitors of ubiquitin-proteasome system. Curr. Cancer Drug Targets, 2014, 14(6), 517-536.
Thawani, S.P.; Tanji, K.; De Sousa, E.A.; Weimer, L.H.; Brannagan, T.H. Bortezomib-associated demyelinating neuropathy--clinical and pathologic features. J. Clin. Neuromuscul. Dis., 2015, 16(4), 202-209.
Luczkowska, K.; Litwinska, Z.; Paczkowska, E.; Machalinski, B. Pathophysiology of drug-induce peripheral neuropathy in patients with multiple myeloma. J. Physiol. Pharmacol., 2018, 69(2)
Lakshman, A.; Modi, M.; Prakash, G.; Malhotra, P.; Khadwal, A.; Jain, S.; Kumari, S.; Varma, N.; Varma, S. Evaluation of bortezomib-induced neuropathy using total neuropathy score (reduced and clinical versions) and NCI CTCAE v4.0 in newly diagnosed patients with multiple myeloma receiving bortezomib-based induction. Clin. Lymphoma Myeloma Leuk., 2017, 17(8), 513-519.
Kaplan, G.S.; Torcun, C.C.; Grune, T.; Ozer, N.K.; Karademir, B. Proteasome inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy as a side effect. Free Radic. Biol. Med., 2017, 103, 1-13.
Carozzi, V.A.; Canta, A.; Chiorazzi, A. Chemotherapy-induced peripheral neuropathy:What do we know about mechanisms? Neurosci. Lett., 2015, 596, 90-107.
Hai, T.; Wolford, C.C.; Chang, Y.S. ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: ismodulation of inflammation a unifying component? Gene Expr., 2010, 15(1), 1-11.
Mallano, T.; Palumbo-Zerr, K.; Zerr, P.; Ramming, A.; Zeller, B.; Beyer, C.; Dees, C.; Huang, J.; Hai, T.; Distler, O.; Schett, G. Distler, J.H. Activating transcription factor 3 regulates canonical TGFβ signalling in systemic sclerosis. Ann. Rheum. Dis., 2016, 75(3), 586-592.
Rau, K.K.; Hill, C.E.; Harrison, B.J.; Venkat, G.; Koenig, H.M.; Cook, S.B.; Rabchevsky, A.G.; Taylor, B.K.; Hai, T.; Petruska, J.C. Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injuryassociated genes in sensory neurons. Exp. Neurol 2016. 283(Pt A), 413-427
Areti, A.; Komirishetty, P.; Akuthota, M.; Malik, R.A.; Kumar, A. Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J. Pineal Res., 2017, 62(3)
Ding, R.; Sun, B.; Liu, Z.; Yao, X.; Wang, H.; Shen, X.; Jiang, H.; Chen, J. Advanced oxidative protein products cause pain hypersensitivity in rats by inducing dorsal root ganglion neurons apoptosis via NADPH oxidase 4/c-Jun N-terminal kinase pathways. Front. Mol. Neurosci., 2017, 10, 195.
Areti, A.; Yerra, V.G.; Naidu, V.; Kumar, A. Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol., 2014, 2, 289-295.
van der Kant, R.; Neefjes, J. Small regulators, major consequences - Ca2+ and cholesterol at the endosome-ER interface. J. Cell Sci., 2014, 127(Pt 5), 929-938.
Díaz-Villanueva, J.F.; Díaz-Molina, R.; García-González, V. Protein folding and mechanisms of proteostasis. Int. J. Mol. Sci., 2015, 16(8), 17193-17230.
Schröder, M. Endoplasmic reticulum stress responses. Cell. Mol. Life Sci., 2008, 65(6), 862-894.
Yin, Y.; Sun, G.; Li, E.; Kiselyov, K.; Sun, D. ER stress and impaired autophagy flux in neuronal degeneration and brain injury. Ageing Res. Rev., 2017, 34, 3-14.
Guo, L.; Hamre, J.; Eldridge, S.; Behrsing, H.P.; Cutuli, F.M.; Mussio, J.; Davis, M. Editor’s highlight: multiparametric image analysis of rat dorsal root ganglion cultures to evaluate peripheral neuropathy-inducing chemotherapeutics. Toxicol. Sci., 2017, 156(1), 275-288.
Bobylev, I.; Peters, D.; Vyas, M.; Barham, M.; Klein, I.; von Strandmann, E.P.; Neiss, W.F.; Lehmann, H.C. Kinesin-5 blocker monastrol protects against bortezomib-induced peripheral neurotoxicity. Neurotox. Res., 2017, 32(4), 555-562.
Bai, X.; Chen, T.; Gao, Y.; Li, H.; Li, Z.; Liu, Z. The protective effects of insulin-like growth factor-1 on neurochemical phenotypes of dorsal rootganglion neurons with BDE-209-induced neurotoxicity in vitro. Toxicol. Ind. Health, 2017, 33(3), 250-264.
Xu, X.; Liu, Z.; Liu, H.; Yang, X.; Li, Z. The effects of galanin on neuropathic pain in streptozotocin-induced diabetic rats. Eur. J. Pharmacol., 2012, 680(1-3), 28-33.
Pfaffl, M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res., 2001, 29(9), e45.
Hunt, D.; Raivich, G.; Anderson, P.N. Activating transcription factor 3 and the nervous system. Front. Mol. Neurosci., 2012, 5, 7.
Galley, H.F.; McCormick, B.; Wilson, K.L.; Lowes, D.A.; Colvin, L.; Torsney, C. Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat. J. Pineal Res., 2017, 63(4)
Karlsson, J.O.G.; Andersson, R.G.; Jynge, P. Mangafodipir a selective cytoprotectant - with special reference to oxaliplatin and its association to chemotherapy-induced peripheral neuropathy (CIPN). Transl. Oncol., 2017, 10(4), 641-649.
Maj, M.A.; Ma, J.; Krukowski, K.N.; Kavelaars, A.; Heijnen, C.J. Inhibition of mitochondrial p53 accumulation by PFT-μ prevents cisplatin-induced peripheral neuropathy. Front. Mol. Neurosci., 2017, 10, 108.
Starobova, H.; Vetter, I. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front. Mol. Neurosci., 2017, 10, 174.
Andoh, T.; Uta, D.; Kato, M.; Toume, K.; Komatsu, K.; Kuraishi, Y. Prophylactic administration of aucubin inhibits paclitaxel-induced mechanical allodynia via the inhibition of endoplasmic reticulum stress in peripheral Schwann cells. Biol. Pharm. Bull., 2017, 40(4), 473-478.
Kumar, S.K.; Laubach, J.P.; Giove, T.J.; Quick, M.; Neuwirth, R.; Yung, G.; Rajkumar, S.V.; Richardson, P.G. Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheralneuropathy in multiple myeloma. Br. J. Haematol., 2017, 178(5), 756-763.
Kerckhove, N.; Collin, A.; Condé, S.; Chaleteix, C.; Pezet, D.; Balayssac, D. Long-term effects, pathophysiological mechanisms, and risk factors of chemotherapy-induced peripheral neuropathies: a comprehensive literature review. Front. Pharmacol., 2017, 8, 86.
Staff, N.P.; Podratz, J.L.; Grassner, L.; Bader, M.; Paz, J.; Knight, A.M.; Loprinzi, C.L.; Trushina, E.; Windebank, A.J. Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons. Neurotoxicology, 2013, 39, 124-131.
Canta, A.; Pozzi, E.; Carozzi, V.A. Mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy (CIPN). Toxic, 2015, 3(2), 198-223.
Carozzi, V.A.; Chiorazzi, A.; Canta, A.; Lapidus, R.G.; Slusher, B.S.; Wozniak, K.M.; Cavaletti, G. Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat. Neurotox. Res., 2010, 17(4), 380-391.
Quartu, M.; Carozzi, V.A.; Dorsey, S.G.; Serra, M.P.; Poddighe, L.; Picci, C.; Boi, M.; Melis, T.; Del Fiacco, M.; Meregalli, C.; Chiorazzi, A.; Renn, C.L.; Cavaletti, G.; Marmiroli, P. Bortezomib treatment produces nocifensive behavior and changes in the expression of TRPV1, CGRP, and substance P in the rat DRG, spinal cord, and sciatic nerve. BioMed Res. Int., 2014, 2014, 180428.
Tonello, R.; Fusi, C.; Materazzi, S.; Marone, I.M.; De Logu, F.; Benemei, S.; Gonçalves, M.C.; Coppi, E.; Castro-Junior, C.J.; Gomez, M.V.; Geppetti, P.; Ferreira, J.; Nassini, R. The peptide Phα1β, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice. Br. J. Pharmacol., 2017, 174(1), 57-69.
Zhang, J.; Su, Y.M.; Li, D.; Cui, Y.; Huang, Z.Z.; Wei, J.Y.; Xue, Z.; Pang, R.P.; Liu, X.G.; Xin, W.J. TNF-α-mediated JNK activation in the dorsal root ganglion neurons contributes to Bortezomib-induced peripheral neuropathy. Brain Behav. Immun., 2014, 38, 185-191.
Liu, C.; Luan, S. OuYang, H.; Huang, Z.; Wu, S.; Ma, C.; Wei, J.; Xin, W. Upregulation of CCL2 via ATF3/c-Jun interaction mediated the Bortezomib-induced peripheral neuropathy. Brain Behav. Immun., 2016, 53, 96-104.
Coelho, A.; Oliveira, R.; Cruz, F.; Cruz, C.D. Impairment of sensory afferents by intrathecal administration of botulinum toxin A improves neurogenic detrusor overactivity in chronic spinal cord injured rats. Exp. Neurol., 2016. 285(Pt B), 159-166.
Chandran, V.; Coppola, G.; Nawabi, H.; Omura, T.; Versano, R.; Huebner, E.A.; Zhang, A.; Costigan, M.; Yekkirala, A.; Barrett, L.; Blesch, A.; Michaelevski, I.; Davis-Turak, J.; Gao, F.; Langfelder, P.; Horvath, S.; He, Z.; Benowitz, L.; Fainzilber, M.; Tuszynski, M.; Woolf, C.J.; Geschwind, D.H. A systems-level analysis of the peripheral nerve intrinsic axonal growth program. Neuron, 2016, 89(5), 956-970.
Gey, M.; Wanner, R.; Schilling, C.; Pedro, M.T.; Sinske, D.; Knöll, B. Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated geneinduction after peripheral nerve injury. Open Biol., 2016, 6(8)
Seijffers, R.; Allchorne, A.J.; Woolf, C.J. The transcription factor ATF-3 promotes neurite outgrowth. Mol. Cell. Neurosci., 2006, 32(1-2), 143-154.
Waseem, M.; Kaushik, P.; Tabassum, H.; Parvez, S. Role of mitochondrial mechanism in chemotherapy-induced peripheral neuropathy. Curr. Drug Metab., 2018, 19(1), 47-54.
Fink, E.E.; Mannava, S.; Bagati, A.; Bianchi-Smiraglia, A.; Nair, J.R.; Moparthy, K.; Lipchick, B.C.; Drokov, M.; Utley, A.; Ross, J.; Mendeleeva, L.P.; Savchenko, V.G.; Lee, K.P.; Nikiforov, M.A. Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors in multiple myeloma cells. Leukemia, 2016, 30(1), 104-111.
Flatters, S.J. The contribution of mitochondria to sensory processing and pain. Prog. Mol. Biol. Transl. Sci., 2015, 131, 119-146.
McCormick, B.; Lowes, D.A.; Colvin, L.; Torsney, C.; Galley, H.F. MitoVitE, a mitochondria-targeted antioxidant, limits paclitaxel-induced oxidative stress and mitochondrial damage in vitro, and paclitaxel-induced mechanical hypersensitivity in a rat pain model. Br. J. Anaesth., 2016, 117(5), 659-666.
Chu, C.; Levine, E.; Gear, R.W.; Bogen, O.; Levine, J.D. Mitochondrial dependence of nerve growth factor-induced mechanical hyperalgesia. Pain, 2011, 152(8), 1832-1837.
Schönthal, A.H. Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientifica, 2012, 2012, 857516.
Kim, I.; Xu, W.; Reed, J.C. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov., 2008, 7(12), 1013-1030.
Dong, L.; Krewson, E.A.; Yang, L.V. Acidosis activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells. Int. J. Mol. Sci., 2017, 18(2), pii E278.
Rzymski, T.; Milani, M.; Pike, L.; Buffa, F.; Mellor, H.R.; Winchester, L.; Pires, I.; Hammond, E.; Ragoussis, I.; Harris, A.L. Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene, 2010, 29(31), 4424-4435.
Liu, Z.; Shi, Q.; Song, X.; Wang, Y.; Wang, Y.; Song, E.; Song, Y. Activating transcription factor 4 (ATF4)-ATF3-C/EBP homologous protein (CHOP) cascade shows an essential role in the ER stress-induced sensitization of tetrachlorobenzoquinone-challenged PC12 cells to ROS-mediated apoptosis via death receptor 5 (DR5) signaling. Chem. Res. Toxicol., 2016, 29(9), 1510-1518.
Berta Qadri, Y.; Tan, P.H.; Ji, R.R. Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain. Expert Opin. Ther. Targets, 2017, 21(7), 695-703.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 13 December, 2018
Page: [50 - 64]
Pages: 15
DOI: 10.2174/1568009618666181003170027
Price: $65

Article Metrics

PDF: 44