JUND-dependent up-regulation of HMOX1 is associated with cisplatin resistance in muscle-invasive bladder cancer.

Abstract

The standard-of-care for metastatic muscle-invasive bladder cancer (MIBC) is platinum-based chemotherapy regimens. Acquired resistance that occurs frequently through unidentified mechanisms, however, remains the major obstacle for implementing therapeutic effectiveness. Here, using data mining and analysis on clinical samples, we show that expression of JUND, a core component of activator protein-1 family, was significantly induced in cisplatin (CDDP)-resistant MIBC. Accumulation of nuclear JUND was associated with low post-chemotherapy survival in MIBC patients. In both genetically engineered cell models and murine xenograft models, we provided evidence that bladder cancer (BC) cells with excessive JUND expression were less responsive to CDDP treatment. This CDDP resistance was further demonstrated to be mediated, at least in part, by transactivation of HMOX1 [the gene encoding heme oxygenase-1 (HO-1)], one of the most important antioxidant signalling pathways of cell adaptation to stress. One mutation within the HMOX1 promoter successfully abolished oxidative stress-enhanced and JUND-driven HMOX1 promoter activation, suggesting that this unique site synergized for maximal HO-1 induction in CDDP-challenged BC cells. Overall, our data highlight an indispensible role of JUND, both as a target as a modifier of the oxidative stress signalling, in conferring an adaptive response during the pathogenesis of CDDP resistance in MIBC.

• Authors: Ye Peng, Yongjie Chen, Shiwei Chen, Jiaolian Wang, Cheng Jiang, Wugang Hou, Chun Xu
• Journal: Journal of biochemistry (J Biochem) Vol. 168 Issue 1 Pg. 73-82 (Jul 01 2020) ISSN: 1756-2651 [Electronic] England
• PMID: 32240302 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Chemical References

• Antineoplastic Agents
• JunD protein, human
• Proto-Oncogene Proteins c-jun
• HMOX1 protein, human
• Heme Oxygenase-1
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Cisplatin (therapeutic use)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Heme Oxygenase-1 (genetics, metabolism)
• Humans
• Mice
• Mice, Nude
• Muscle Neoplasms (genetics, metabolism, pathology)
• Prognosis
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Signal Transduction
• Survival Rate
• Up-Regulation
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)