The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells

Thomas R. Johnson, Kimberley Stone, Malti Nikrad, Tammie Yeh, Wei Xing Zong, Craig B. Thompson, Alexandre Nesterov, Andrew Kraft

Research output: Contribution to journalArticle

170 Citations (Scopus)

Abstract

We demonstrate that PS-341, a small molecule inhibitor of the proteasome, markedly sensitizes resistant prostate, colon, and bladder cancer cells to TNF-like apoptosis-inducing ligand (TRAIL)-induced apoptosis irrespective of Bcl-xL overexpression. PS-341 treatment by itself does not affect the levels of Bax, Bak, caspases 3 and 8, c-Flip or FADD, but elevates levels of TRAIL receptors DR4 and DR5. This increase in receptor protein levels is associated with the ubiquitination of the DR5 protein. When PS-341 is combined with TRAIL, the levels of activated caspase 8 and cleaved Bid are substantially increased. In Bax-negative TRAIL-resistant HC-4 colon cancer cells, the combination of PS-341 and TRAIL overcomes the block to activation of the mitochondrial pathway and causes SMAC and cytochrome c release followed by apoptosis. Similarly, murine embryonic fibroblasts lacking Bax undergo apoptosis when exposed to the combination of PS-341 and TRAIL; however, fibroblasts lacking Bak are significantly resistant. Taken together, these findings indicate that PS-341 enhances TRAIL-induced apoptosis by increasing the cleavage of caspase 8, causing Bak-dependent release of mitochondrial proapoptotic proteins.

Original languageEnglish (US)
Pages (from-to)4953-4963
Number of pages11
JournalOncogene
Volume22
Issue number32
DOIs
StatePublished - Aug 7 2003
Externally publishedYes

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Proteasome Inhibitors
Caspase 9
Caspase 8
Apoptosis
Colonic Neoplasms
Fibroblasts
TNF-Related Apoptosis-Inducing Ligand Receptors
Ubiquitination
Mitochondrial Proteins
Cytochromes c
Urinary Bladder Neoplasms
Caspase 3
Bortezomib
Prostatic Neoplasms
Proteins
Ligands

Keywords

  • Apoptosis
  • Bax
  • Bcl-2
  • PS-341
  • TRAIL

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. / Johnson, Thomas R.; Stone, Kimberley; Nikrad, Malti; Yeh, Tammie; Zong, Wei Xing; Thompson, Craig B.; Nesterov, Alexandre; Kraft, Andrew.

In: Oncogene, Vol. 22, No. 32, 07.08.2003, p. 4953-4963.

Research output: Contribution to journalArticle

Johnson, TR, Stone, K, Nikrad, M, Yeh, T, Zong, WX, Thompson, CB, Nesterov, A & Kraft, A 2003, 'The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells', Oncogene, vol. 22, no. 32, pp. 4953-4963. https://doi.org/10.1038/sj.onc.1206656
Johnson, Thomas R. ; Stone, Kimberley ; Nikrad, Malti ; Yeh, Tammie ; Zong, Wei Xing ; Thompson, Craig B. ; Nesterov, Alexandre ; Kraft, Andrew. / The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. In: Oncogene. 2003 ; Vol. 22, No. 32. pp. 4953-4963.
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