Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells

Juan J. Gu, Gregory P. Kaufman, Cory Mavis, Myron S. Czuczman, Francisco J. Hernandez-Ilizaliturri

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 rituximabsensitive (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 BTZinduced 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.

Original languageEnglish (US)
Pages (from-to)12741-12753
Number of pages13
JournalOncotarget
Volume8
Issue number8
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • B-cell lymphoma
  • Bortezomib
  • Rituximab

ASJC Scopus subject areas

  • Oncology

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