Research Papers:
Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells
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Abstract
Juan J. Gu1,2, Gregory P. Kaufman3, Cory Mavis1,2, Myron S Czuczman4, Francisco J. Hernandez-Ilizaliturri1,2
1Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
2Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA
3Department of Internal Medicine, Mayo Clinic, Rochester, MN, Celgene Corporation, Summit, NJ, USA
Correspondence to:
Francisco J. Hernandez-Ilizaliturri, email: [email protected]
Keywords: bortezomib, B-cell lymphoma, rituximab
Received: March 29, 2016 Accepted: December 05, 2016 Published: December 31, 2016
ABSTRACT
The ubiqutin-proteasome system (UPS) plays a role in rituximab-chemotherapy resistance and bortezomib (BTZ) possesses caspase-dependent (i.e. Bak stabilization) and a less characterized caspase–independent mechanism-of-action(s). Here, we define BTZ-induced caspase-independent cell death pathways. A panel of rituximab-sensitive (RSCL), rituximab-resistant cell lines (RRCL) and primary tumor cells derived from lymphoma patients (N = 13) were exposed to BTZ. Changes in cell viability, cell-cycle, senescence, and mitotic index were quantified. In resting conditions, RRCL exhibits a low-proliferation rate, accumulation of cells in S-phase and senescence. Exposure of RRCL to BTZ reduces cell senescence, induced G2-M phase cell-cycle arrest, and is associated with mitotic catastrophe. BTZ stabilized p21, CDC2, and cyclin B in RRCL and in primary tumor cells. Transient p21 knockdown alleviates BTZ-induced senescence inhibition, G2-M cell cycle blockade, and mitotic catastrophe. Our data suggest that BTZ can induce apoptosis or mitotic catastrophe and that p21 has a pivotal role in BTZ activity against RRCL.
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