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Slow down to stay alive†
HER4 protects against cellular stress and confers chemoresistance in neuroblastoma
Version of Record online: 13 MAR 2012
Copyright © 2012 American Cancer Society
Volume 118, Issue 20, pages 5140–5154, 15 October 2012
How to Cite
Hua, Y., Gorshkov, K., Yang, Y., Wang, W., Zhang, N. and Hughes, D. P. M. (2012), Slow down to stay alive. Cancer, 118: 5140–5154. doi: 10.1002/cncr.27496
Electron microscopy was conducted by Kenneth Dunner, Jr., in the High-Resolution Electron Microscopy Facility at the University of Texas M. D. Anderson Cancer Center (MDACC). Microarray analysis was done with the help of Qiuyu Wu and Kim Seung Wook from Dr. Fidler's laboratory at MDACC.
- Issue online: 5 OCT 2012
- Version of Record online: 13 MAR 2012
- Manuscript Accepted: 19 JAN 2012
- Manuscript Revised: 18 JAN 2012
- Manuscript Received: 18 OCT 2011
- human epidermal growth factor receptor 4;
- v-erb-a erythroblastic leukemia viral oncogene homolog;
- cellular stress;
- multicellular tumor sphere
Neuroblastoma (NBL) is a common pediatric solid tumor, and outcomes for patients with advanced neuroblastoma remain poor despite extremely aggressive treatment. Chemotherapy resistance at relapse contributes heavily to treatment failure. The poor survival of patients with high-risk NBL prompted this investigation into novel treatment options with the objective of gaining a better understanding of resistance mechanisms. On the basis of previous work and on data from publicly available studies, the authors hypothesized that human epidermal growth factor receptor 4 (Her4) contributes to resistance.
Her4 expression was reduced with small-hairpin RNA (shRNA) to over express intracellular HER4, and the authors tested its impact on tumor cell survival under various culture conditions. The resulting changes in gene expression after HER4 knockdown were measured by using a messenger RNA (mRNA) array.
HER4 expression was up-regulated in tumor spheres compared with the expression in monolayer culture. With HER4 knockdown, NBL cells became less resistant to anoikis and serum starvation. Moreover, HER4 knockdown increased the chemosensitivity of NBL cells to cisplatin, doxorubicin, etoposide, and activated ifosfamide. In mRNA array analysis, HER4 knockdown predominately altered genes related to cell cycle regulation. In NBL spheres compared with monolayers, cell proliferation was decreased, and cyclin D expression was reduced. HER4 knockdown reversed cyclin D suppression. Overexpressed intracellular HER4 slowed the cell cycle and induced chemoresistance.
The current results indicated that HER4 protects NBL cells from multiple exogenous apoptotic stimuli, including anoikis, nutrient deficiency, and cytotoxic chemotherapy. The intracellular fragment of HER4 was sufficient to confer this phenotype. HER4 functions as a cell cycle suppressor, maintaining resistance to cellular stress. The current findings indicate that HER4 overexpression may be associated with refractory disease, and HER4 may be an important therapeutic target. Cancer 2012. © 2012 American Cancer Society.