MITOGENIC SIGNALING IN ANDROGEN SENSITIVE AND INSENSITIVE PROSTATE CANCER CELL LINES

GUO, CHUANHAI
LUTTRELL, LOUIS M.
PRICE, DAVID T.

From the Departments of Surgery, Medicine, Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
* Requests for reprints: Medical Science Research Building, P.O. Box 2621, Duke University Medical Center, Durham, NC 27710.

Accepted for publication September 28, 1999.

Supported by an American Foundation of Urology Diseases Research Scholar Award, NIH Grant DK0258A and NIH Grant DK02352.

Journal of Urology 163(3):p 1027, March 2000.

Purpose:

To investigate the role of a specific mitogen activated protein kinase, extracellular signal-regulated kinase (ERK), in regulating cell proliferation induced by three potentially important prostate cancer mitogens that signal via different classes of receptors.

Materials and Methods:

Androgen sensitive (LNCaP) and insensitive (PC-3) prostate cancer cell lines were used in these studies. Epidermal growth factor (EGF), lysophosphatidic acid (LPA), and dihydrotestosterone (DHT) were the mitogenic stimulants and AG1478, a receptor tyrosine kinase inhibitor, and PD98059, an inhibitor of MEK, were the chemical inhibitors used in this study. Cell proliferation was measured using the WST-1 assay and ERK expression and activation was determined by immunoblotting for phospho- and total ERK.

Results:

In androgen-sensitive LNCaP cells, epidermal growth factor (EGF) and dihydrotestosterone (DHT) both enhanced cell proliferation. EGF-stimulation dramatically increased ERK phosphorylation while DHT did not. In the androgen-insensitive cell line, PC-3, EGF- and LPA- induced ERK phosphorylation and cell proliferation. Inhibition of EGF- and LPA- induced ERK activation with the EGF receptor inhibitor, AG1478, or the MEK inhibitor, PD98059, attenuated their proliferative effects. Neither inhibitor had an effect on DHT stimulated cell proliferation.

Conclusions:

These data demonstrate heterogeneity of mitogenic signaling in prostate cancer cells, and support the hypothesis that androgens and growth factors utilize divergent signaling pathways in prostate cancer to induce proliferation.