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Apoptosis signaling by the novel compound 3-Cl-AHPC involves increased EGFR proteolysis and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase activities

Oncogene volume 23, pages 1874–1884 (2004)Cite this article

Abstract

The threonine and serine protein kinase AKT plays a major role in inhibiting apoptosis in a number of malignant cell types including prostate and breast carcinoma. Activation of AKT is a complex process involving translocation to the plasma membrane and phosphorylation of serine and threonine amino-acid residues. We now report that the novel compound 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), induces apoptosis in breast and prostate carcinoma cells and inhibits AKT activity in these cells. Overexpression of a constitutively activated AKT inhibits 3-Cl-AHPC-mediated apoptosis. Decrease in AKT activity occurs through 3-Cl-AHPC inhibition of phosphatidylinositol 3 kinase (PI3-K) activity. 3-Cl-AHPC inhibits PI3-K activity by enhancing epidermal growth factor receptor (EGFR) proteolysis and thus inhibiting EGFR association with the p85 subunit of PI3-K. 3-Cl-AHPC-mediated decrease in PI3-K activity results in the reduced synthesis of phosphatidylinositol 3,4 bisphosphate and phosphatidylinositol 3,4,5 triphosphate with the subsequent inhibition of integrin-linked kinase activity and serine-473 phosphorylation of AKT. Overexpression of EGFR results in increased AKT activity and inhibition of 3-Cl-AHPC-mediated decrease in AKT activation, AKT activity and 3-Cl-AHPC-mediated apoptosis. Inhibition of AKT activity by this compound results in the inability of AKT to phosphorylate and inactivate the proapoptotic forkhead transcription factor.

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Abbreviations

AHPN/CD437:

6-[3-(1-adamantly)-4-hydroxyphenyl]-2-naph-thalene carboxylic acid

3-Cl-AHPC:

4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid

EGFR:

epidermal growth factor receptor

ILK:

integrin-linked kinase

PI3-K:

phosphatidylinositol 3 kinase

PtdIns (3,4)P2:

phosphatidylinositol bisphosphate

PtdIns (3,4,5)P3:

phosphatidylinositol triphosphate

FKHR:

forkhead transcription factor

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Acknowledgements

We thank Bill Browning for preparation of the figures and Donna Bennett for excellent secretarial assistance. This study was supported by grants from Medical Research Services of the Department of Veteran Affairs (JAF, AKR) and NIH (P01 CA51993) (MID, JAF).

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Authors and Affiliations

  1. Department of Internal Medicine, John D Dingell VA Medical Center, Karmanos Cancer Institute, Wayne State University, Detroit, 48201, MI, USA

    Lulu Farhana, Yuxiang Zhang, Arun K Rishi & Joseph A Fontana

  2. Burnham Institute, La Jolla, 92037, CA, USA

    Marcia I Dawson

  3. Department of Pharmacology, Upstate Medical University, State University of New York, Syracuse, 13210, NY, USA

    Ying Huang

  4. Department of Pathology, Wayne State University, Detroit, 48201, MI, USA

    Kaladhar B Reddy

  5. Department of Pharmacology and Physiology, University of Rochester, Rochester, 14642, NY, USA

    Robert S Freeman

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  1. Lulu Farhana
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Correspondence to Joseph A Fontana.

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Farhana, L., Dawson, M., Huang, Y. et al. Apoptosis signaling by the novel compound 3-Cl-AHPC involves increased EGFR proteolysis and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase activities. Oncogene 23, 1874–1884 (2004). https://doi.org/10.1038/sj.onc.1207311

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