Get access

Neuroendocrine-derived peptides promote prostate cancer cell survival through activation of IGF-1R signaling

Authors

  • John O. DaSilva,

    1. Department of Microbiology, Cancer Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
    Search for more papers by this author
  • George P. Amorino,

    1. Department of Radiation Oncology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
    Search for more papers by this author
  • Eli V. Casarez,

    1. Department of Microbiology, Cancer Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
    Search for more papers by this author
  • Bradley Pemberton,

    1. Department of Radiation Oncology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
    Search for more papers by this author
  • Sarah J. Parsons

    Corresponding author
    1. Department of Microbiology, Cancer Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
    • Department of Microbiology, University of Virginia Health System, PO Box 800734, Charlottesville, VA 22908-0734.
    Search for more papers by this author

  • Conflict of interest: The authors declare no conflict of interest.

Abstract

BACKGROUND

Neuroendocrine (NE) cells promote the progression of prostate cancer to a castration-resistant state through the production of paracrine growth factors. We have demonstrated this principle using in vitro and in vivo proliferative endpoints; however, the contributions of NE-derived pro-survival factors and anti-apoptosis to this phenomenon have not been thoroughly investigated.

METHODS

Here, we utilized conditioned-medium (CM) from LNCaP cells, engineered to undergo NE differentiation, and examined its effects on PC3 and LNCaP cell survival.

RESULTS

Statistically significant changes in clonogenic survival, Annexin V staining, PARP cleavage and trypan blue positivity of approximately twofold were observed in the presence of NE-derived CM relative to control-CM for both LNCaP and PC3 cells. These changes were partially abrogated by antagonists of the neuropeptides neurotensin, bombesin, and PTHrP. Selective inhibitors of IGF-1R, EGFR or Src caused significant and nearly complete blockade of prostate cancer cell survival due to NE secretions. Similar increases in cell survival were observed for LNCaP or PC3 cells treated with NE-derived medium in the presence of docetaxel. Increased phosphorylation of IGF-1R, following treatment with NE-derived medium, was accompanied by decreased protein tyrosine phosphatase, receptor type F (PTPRF) mRNA, and protein levels. Overexpression of PTPRF decreased cell survival, the amplitude and duration of IGF-1R phosphorylation, and enhanced PARP cleavage in the presence of NE-derived medium.

CONCLUSIONS

These data support the hypothesis that NE-derived factors act upon prostate cancer cells to stimulate pro-survival signaling and describe a novel mechanism of cross-talk between NE-derived factors and IGF-1R, mediated in part by PTPRF. Prostate 73: 801–812, 2013. © 2012 Wiley Periodicals, Inc.

Ancillary