Apoptosis signaling by the novel compound 3-Cl-AHPC involves increased EGFR proteolysis and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase activities.
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.
John D Dingell VA Medical Center, Karmanos Cancer Institute, Department of Internal Medicine, Wayne State University, Detroit, MI 48201, USA.
Lulu
L
Farhana
Marcia I
MI
Dawson
Ying
Y
Huang
Yuxiang
Y
Zhang
Arun K
AK
Rishi
Kaladhar B
KB
Reddy
Robert S
RS
Freeman
Joseph A
JA
Fontana
D000218:Adamantane / Q000031:analogs & derivatives / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000633:toxicity*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
D000218:Adamantane; D002934:Cinnamates; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; C494918:AKT1 protein, human