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Author Notes:

*Corresponding Author: Dong M. Shin, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322. Phone: 1-404-778-2980, Fax: 1-404-778-5520. dmshin@emory.edu.

Authors' Affiliations Department of Hematology and Medical Oncology, Winship Cancer Institute; Departments of Biostatistics and Bioinformatics, Pathology, and Radiation Oncology, Emory University, Atlanta, Georgia.

Authors' Contributions: Conception and design: M.A. Rahman, A.R.M. Ruhul Amin, X. Deng, Z.G. Chen, D.M. Shin Development of methodology: M.A. Rahman, A.R.M. Ruhul Amin, Z.G. Chen, D.M. Shin Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M.A. Rahman, A.R.M. Ruhul Amin, D. Wang, L. Koenig, S. Nannapaneni, G.L. Sica, D.M. Shin Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.A. Rahman, A.R.M. Ruhul Amin, S. Nannapaneni, Z. Chen, Z. Wang, X. Deng, Z.G. Chen, D.M. Shin Writing, review, and/or revision of the manuscript: M.A. Rahman, A.R. M. Ruhul Amin, S. Nannapaneni, Z. Chen, Z. Wang, X. Deng, Z.G. Chen, D.M. Shin Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): M.A. Rahman Study supervision: M.A. Rahman, A.R.M. Ruhul Amin, Z.G. Chen, D.M. Shin.

The authors thank Dr. Mark Davis and Dr. Yun Yen for supplying reagents. The authors also thank Dr. Anthea Hammond for her critical and editorial review of this article.

No potential conflicts of interest were disclosed.

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Research Funding:

This work was supported by NIH/NCI grant U54 CA119338-04, P50 CA128613 (Head and Neck Cancer SPORE). Drs. DM Shin and Z(G) Chen are recipients of Georgia Cancer Coalition (GCC) Distinguished Scholar Awards.

Keywords:

  • RRM2
  • Bcl-2
  • RNAi
  • Apoptosis

RRM2 Regulates Bcl-2 in Head and Neck and Lung Cancers: A Potential Target for Cancer Therapy

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Journal Title:

Clinical Cancer Research

Volume:

Volume 19, Number 13

Publisher:

, Pages 3416-3428

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Purpose Ribonucleotide reductase subunit M2 (RRM2) plays an active role in tumor progression. Recently, we reported that depletion of RRM2 by systemic delivery of a nanoparticle carrying RRM2-specific siRNA suppresses head and neck tumor growth. The aim of this study is to clarify the underlying mechanism by which RRM2 depletion inhibits tumor growth. Methods siRNA-mediated gene silencing was performed to downregulate RRM2. Immunoblotting, RT-PCR, confocal microscopy, tissue fractionation, gene overexpression and knockdown were employed to analyze critical apoptosis signaling. Conventional immunohistochemistry (IHC) and quantum dot-based IHF were applied to detect RRM2 and Bcl2 expression and localization in tissue samples from patients and mice. Results Knockdown of RRM2 led to apoptosis through the intrinsic pathway in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. We demonstrated that Bcl-2 is a key determinant controlling apoptosis, both in vitro and in vivo and that RRM2 depletion significantly reduces Bcl-2 protein expression. We observed that RRM2 regulates Bcl-2 protein stability, with RRM2 suppression leading to increased Bcl-2 degradation, and identified their co-localization in HNSCC and NSCLC cells. In a total of 50 specimens each from HNSCC and NSCLC patients, we identified the co-localization of Bcl-2 and RRM2 and found a significant positive correlation between their expression in HNSCC (R=0.98, p<0.0001) and NSCLC (R=0.92, p<0.0001) tumor tissues. Conclusion Our novel findings add to the knowledge of RRM2 in regulating expression of the anti-apoptotic protein Bcl-2 and reveal a critical link between RRM2 and Bcl-2 in apoptosis signaling.

Copyright information:

© 2013 American Association for Cancer Research.

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