Human THP-1 monocytic leukemic cells induced to undergo monocytic differentiation by bryostatin 1 are refractory to proteasome inhibitor-induced apoptosis

C. Chen, H. Lin, C. Karanes, George Pettit, B. D. Chen

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The ubiquitin-proteasome pathway is the principal mechanism for the degradation of short-lived proteins in eukaryotic cells. We demonstrated that treatment of THP-1 human monocytic leukemia cells with Z-LLL-CHO, a reversible proteasome inhibitor, induced cell death through an apoptotic pathway. Apoptosis in THP-1 cells induced by Z-LLL-CHO involved a cytochrome c-dependent pathway, which included the release of mitochondrial cytochrome c, activation of caspase-9 and -3, and cleavage of Bcl-2 into a shortened 22-kDa fragment. Induction of apoptosis by protease inhibitor also was detected in U937 and TF-1 leukemia cell lines and cells obtained from acute myelogenous leukemia patients but not in normal human blood monocytes. Treatment of human blood monocytes with Z-LLL-CHO did not induce apoptosis or Bcl-2 cleavage in these cells that rarely proliferate. Interestingly, when THP-1 cells were induced to undergo monocytic differentiation by bryostatin 1, a naturally occurring protein kinase C activator, they were no longer susceptible to apoptosis induced by Z-LLL-CHO. Bryostatin 1-induced differentiation of THP-1 cells was associated with growth arrest, acquisition of adherent capacity, and expression of membrane markers characteristic of blood monocytes. Likewise, differentiated THP-1 cells were refractory to Z-LLL-CHO-induced cytochrome c release, caspase activation, and Bcl-2 cleavage. Resistance to Z-LLL-CHO-induced apoptosis in differentiated THP-1 cells was not due to cell cycle arrest. These findings show that the action of proteasome inhibitors is mediated primarily through a cytochrome c-dependent pathway and induces apoptosis in leukemic cells that are not differentiated.

Original languageEnglish (US)
Pages (from-to)4377-4385
Number of pages9
JournalCancer Research
Volume60
Issue number16
StatePublished - Aug 15 2000
Externally publishedYes

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Proteasome Inhibitors
Apoptosis
Cytochromes c
Monocytes
Leukemia
bryostatin 1
Caspase 9
Eukaryotic Cells
Proteasome Endopeptidase Complex
Caspases
Ubiquitin
Cell Cycle Checkpoints
Protease Inhibitors
Acute Myeloid Leukemia
Caspase 3
Protein Kinase C
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Cell Death
Cell Line
Membranes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Human THP-1 monocytic leukemic cells induced to undergo monocytic differentiation by bryostatin 1 are refractory to proteasome inhibitor-induced apoptosis. / Chen, C.; Lin, H.; Karanes, C.; Pettit, George; Chen, B. D.

In: Cancer Research, Vol. 60, No. 16, 15.08.2000, p. 4377-4385.

Research output: Contribution to journalArticle

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