1. ¹Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA
2. ²Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198, USA
3. ³Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA
4. ⁴Section of Urologic Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA

Correspondence: M-F Lin, E-mail: mlin@unmc.edu

⁵These two authors contributed equally to this article

⁶Current address: Department of Urology, Nagasaki University School of Medicine, Sakamoto 1-7-1 Nagasaki 852-8501, Japan

⁷Current address: Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

⁸Current address: School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA

Received 17 December 2004; Revised 4 May 2005; Accepted 4 May 2005; Published online 19 September 2005.

Abstract

p66^Shc, an isoform of Shc adaptor proteins, is shown to mediate various signals, including cellular stress. However, little is known about its involvement in carcinogenesis. We previously showed that p66^Shc protein level is upregulated by steroid hormones in human carcinoma cells and is higher in prostate cancer (PCa) specimens than adjacent noncancerous cells. In this study, we investigated the role of p66^Shc protein in PCa cell proliferation. Among different PCa cell lines tested, p66^Shc protein level showed positive correlation with cell proliferation, that is, rapid-growing cells expressed higher p66^Shc protein than slow-growing cells. Exposure of slow-growing LNCaP C-33 cells to epidermal growth factor (EGF) and 5-dihydrotestosterone (DHT) led to upregulation of proliferation and p66^Shc protein level. Conversely, growth suppression of fast-growing cells by cellular form of prostatic acid phosphatase (cPAcP) expression, a negative growth regulator, downregulated their p66^Shc protein level. Additionally, increased expression of p66^Shc protein by cDNA transfection in LNCaP C-33 cells resulted in increased cell proliferation. Cell cycle analyses showed higher percentage of p66^Shc-overexpressing cells at S phase (24%) than control cells (17%), correlating with their growth rates. On the other hand, transient knock-down of p66^Shc expression by RNAi in rapidly growing cells decreased their proliferation as evidenced by the reduced cell growth as well as S phase in p66^Shc-knocked down cells. The p66^Shc signaling in cell growth regulation is apparently mediated by extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK). Thus, our results indicate a novel role for p66^Shc in prostate carcinogenesis, in part, promoting cell proliferation.