Research Papers:
Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells
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Abstract
Stephen L. Abrams1,*, Peter P. Ruvolo2,3,*, Vivian R. Ruvolo2,3, Giovanni Ligresti4,5, Alberto M. Martelli6, Lucio Cocco6, Stefano Ratti6, Agostino Tafuri7, Linda S. Steelman1, Saverio Candido4, Massimo Libra4,# and James A. McCubrey1,#
1Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
2Section of Signal Transduction and Apoptosis, Hormel Institute, University of Minnesota, Austin, MN, USA
3Current/Present address: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
4Department of Biomedical and Biotechnological Sciences, Pathology and Oncology Section, University of Catania, Catania, Italy
5Current/Present address: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA
6Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy
7Hematology, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy
*Co-First Authors
# Co-Last Authors
Correspondence to:
James A. McCubrey, email: [email protected]
Massimo Libra, email: [email protected]
Keywords: TP53, chemosensitivity, drug sensitivity, apoptosis, nutlin-3a
Received: July 12, 2017 Accepted: August 15, 2017 Published: August 24, 2017
ABSTRACT
A critical problem in leukemia as well as other cancer therapies is the development of chemotherapeutic drug-resistance. We have developed models of hematopoietic drug resistance that are based on expression of dominant-negative TP53 [TP53 (DN)] or constitutively-active MEK1 [MEK1(CA)] oncogenes in the presence of chemotherapeutic drugs. In human cancer, functional TP53 activity is often lost in human cancers. Also, activation of the Raf/MEK/ERK pathway frequently occurs due to mutations/amplification of upstream components of this and other interacting pathways. FL5.12 is an interleukin-3 (IL−3) dependent hematopoietic cell line that is sensitive to doxorubicin (a.k.a Adriamycin). FL/Doxo is a derivative cell line that was isolated by culturing the parental FL5.12 cells in doxorubicin for prolonged periods of time. FL/Doxo + TP53 (DN) and FL/Doxo + MEK1 (CA) are FL/Doxo derivate cell lines that were infected with retrovirus encoding TP53 (DN) or MEK1 (CA) and are more resistant to doxorubicin than FL/Doxo cells. This panel of cell lines displayed differences in the sensitivity to inhibitors that suppress mTORC1, BCL2/BCLXL, MEK1 or MDM2 activities, as well as, the proteasomal inhibitor MG132. The expression of key genes involved in cell growth and drug-resistance (e.g., MDM2, MDR1, BAX) also varied in these cells. Thus, we can begin to understand some of the key genes that are involved in the resistance of hematopoietic cells to chemotherapeutic drugs and targeted therapeutics.
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