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Expression of p66Shc protein correlates with proliferation of human prostate cancer cells

Abstract

p66Shc, 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 p66Shc 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 p66Shc protein in PCa cell proliferation. Among different PCa cell lines tested, p66Shc protein level showed positive correlation with cell proliferation, that is, rapid-growing cells expressed higher p66Shc protein than slow-growing cells. Exposure of slow-growing LNCaP C-33 cells to epidermal growth factor (EGF) and 5α-dihydrotestosterone (DHT) led to upregulation of proliferation and p66Shc protein level. Conversely, growth suppression of fast-growing cells by cellular form of prostatic acid phosphatase (cPAcP) expression, a negative growth regulator, downregulated their p66Shc protein level. Additionally, increased expression of p66Shc protein by cDNA transfection in LNCaP C-33 cells resulted in increased cell proliferation. Cell cycle analyses showed higher percentage of p66Shc-overexpressing cells at S phase (24%) than control cells (17%), correlating with their growth rates. On the other hand, transient knock-down of p66Shc expression by RNAi in rapidly growing cells decreased their proliferation as evidenced by the reduced cell growth as well as S phase in p66Shc-knocked down cells. The p66Shc 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 p66Shc in prostate carcinogenesis, in part, promoting cell proliferation.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

Ab:

antibody

cPAcP:

cellular form of prostatic acid phosphatase

DHT:

5α-dihydrotestosterone

ECL:

enhanced chemiluminescence

EGF:

epidermal growth factor

ERK/MAPK:

extracellular signal-regulated kinases/mitogen-activated protein kinases

FBS:

fetal bovine serum

GFP:

green fluorescent protein

PCa:

prostate cancer

ROS:

reactive oxygen species

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Acknowledgements

We thank Dr Pier Giuseppe Pelicci at European Institute of Oncology (Milan, Italy) and Dr A Raymond Frackelton Jr at Brown University (Providence, RI) for the gift of the wild-type p66Shc cDNA; Dr Jin-Tang Dong at Emory University School of Medicine (Atlanta, GA) for TSU-Pr1 cell line. We thank Ms Jacquelynn Dahl's help for screening p66Shc stable subclone cells. We also thank the supports from the core facilities, including Molecular Biology, DNA sequencing, Tissue Procurement and Flow Cytometry at UNMC. This study was supported in part by NIH grant CA88184, P20RR017675, P20RR018759, NCI P30 CA36727, Department of Defense PC040587 and PC05096, and the Graduate Student Fellowship of UNMC.

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Correspondence to Ming-Fong Lin.

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Veeramani, S., Igawa, T., Yuan, TC. et al. Expression of p66Shc protein correlates with proliferation of human prostate cancer cells. Oncogene 24, 7203–7212 (2005). https://doi.org/10.1038/sj.onc.1208852

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Keywords

  • p66Shc
  • prostatic acid phosphatase
  • prostate cancer
  • cell proliferation

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