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Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer

Oncogene volume 20, pages 6073–6083 (2001)Cite this article

Abstract

TRAIL/Apo-2L is a member of the tumor necrosis factor superfamily and has recently been shown to induce apoptosis in cancer cells, but not in normal cells. In nude mice injected with human tumors, TRAIL reduces the size of these tumors without side effects. Akt promotes cell survival and block apoptosis. Some prostate cancer cells express high levels of Akt due to lack of active lipid phosphatase PTEN, a negative regulator of PI-3 kinase pathway, which may be responsible for drug resistance. The objective of this paper is to investigate the intracellular molecules that regulate TRAIL resistance. We have examined caspase-8 activity, BID cleavage, Akt activity, mitochondrial membrane potential (ΔΨm) and apoptosis in prostate cancer (LNCap, PC-3, PC-3M and DU145) cells treated with or without TRAIL. PC-3, PC-3M and DU145 cells are sensitive to TRAIL, whereas LNCap cells are resistant. LNCap cells express the highest level of constitutively active Akt, which is directly correlated with TRAIL resistance. TRAIL activates caspase-8 in all the cell lines. Downregulation of constitutively active Akt by PI-3 kinase inhibitors (wortmannin and LY-294002), dominant negative Akt or PTEN, renders LNCap cells sensitive to TRAIL. Inhibition of TRAIL sensitivity occurs at the level of BID cleavage. Inhibition of protein synthesis by cycloheximide also causes LNCap cells sensitive to TRAIL. Overexpression of Bcl-2 or Bcl-XL inhibits TRAIL-induced ΔΨm and apoptosis. Overexpression of constitutively active Akt in PC-3M cells (express very low levels of constitutively active Akt) restores TRAIL resistance. These data suggest that elevated Akt activity protects LNCap cells from TRAIL-induced apoptosis, and the PI-3 kinase/Akt pathway may inhibit apoptotic signals by inhibiting processing of BID. Thus, constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer.

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Acknowledgements

We extend our sincere thanks to Dr Stanley Korsmeyer (Dana-Farber Cancer Institute, Boston, MA) for providing the Bcl-2 and Bcl-XL expression vector. We also thank Dr William Sellers (Dana-Farber Cancer Institute, Boston, MA) for providing PTEN expression vector.

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  1. Department of Pharmaceutical Sciences, University of Maryland - School of Pharmacy, Greenebaum Cancer Center, 20 N Pine Street, Baltimore, MD 21201-1180, Maryland, USA

    Xufeng Chen, Hitesh Thakkar, Frazier Tyan, Suzanna Gim, Heather Robinson, Calvin Lee, Chichi Nwokorie, Nneka Onwudiwe & Rakesh K Srivastava

  2. Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Box 23, Baltimore, MD 21224-6825, Maryland, USA

    Sanjay K Pandey

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Chen, X., Thakkar, H., Tyan, F. et al. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 20, 6073–6083 (2001). https://doi.org/10.1038/sj.onc.1204736

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