Akt inactivates ERK causing decreased response to chemotherapeutic drugs in advanced CaP cells.
Activation of the PI3K/Akt signaling cascade is often associated with advanced forms of prostatic carcinoma (CaP). This is likely explained by the common loss of the PTEN gene in a majority of CaP patients. Conversely, activation of the Raf/MEK/ERK pathway is seldom linked with prostatic disease. The interplay between these two pathways in advanced CaP has not been established. The following manuscript demonstrates that Akt can directly associate with Raf-1 causing its inactivation via phosphorylation of a negative regulatory residue (serine 259). Inhibition of PI3K with either LY294002 and wortmannin was sufficient to cause upregulation of ERK activity as measured by immunoblotting. Prolonged treatment with two commonly-used chemotoxic compounds, doxorubicin and paclitaxel, caused increased activation of ERK in PTEN-positive DU145 cells, but not PTEN-negative PC3 cells. Others have reported that ERK activation is essential for drug-induced death, which, when combined with these data, supports the notion that Akt plays an integral role in the response of prostate cancer cells to chemotherapeutic drugs. These results demonstrate that, in prostate cancer cells, the efficacy of chemotherapy may be limited by its effects on the intracellular signaling pathways found within the cell. The genotype of the tumor must be considered for an effective response to these and other antineoplastic drugs.
Lee
John T
JT
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, USA.
Steelman
Linda S
LS
Chappell
William H
WH
McCubrey
James A
JA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010768:Phosphoserine; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human