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 S. Kraft

Research output: Contribution to journalArticle

170 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells'. Together they form a unique fingerprint.

  • Cite this

    Johnson, T. R., Stone, K., Nikrad, M., Yeh, T., Zong, W. X., Thompson, C. B., Nesterov, A., & Kraft, A. S. (2003). The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene, 22(32), 4953-4963. https://doi.org/10.1038/sj.onc.1206656