Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer Journal Article


Authors: Carver, B.; Chapinski, C.; Wongvipat, J.; Hieronymus, H.; Chen, Y.; Chandarlapaty, S.; Arora, V.; Le, C.; Koutcher, J.; Scher, H.; Scardino, P.; Rosen, N.; Sawyers, C.
Article Title: Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer
Abstract: Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival. © 2011 Elsevier Inc.
Keywords: nonhuman; animal cell; mouse; animal tissue; cell survival; animal experiment; phosphatidylinositol 3 kinase; prostate cancer; oncogene; xenograft; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; tumor cell; androgen receptor; feedback system; negative feedback
Journal Title: Cancer Cell
Volume: 19
Issue: 5
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2011-05-17
Start Page: 575
End Page: 586
Language: English
DOI: 10.1016/j.ccr.2011.04.008
PROVIDER: scopus
PUBMED: 21575859
PMCID: PMC3142785
DOI/URL:
Notes: --- - "Export Date: 23 June 2011" - "CODEN: CCAEC" - "Source: Scopus"
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MSK Authors
  1. Charles L Sawyers
    201 Sawyers
  2. Neal Rosen
    406 Rosen
  3. Peter T Scardino
    660 Scardino
  4. Yu Chen
    104 Chen
  5. Vivek Kumar Arora
    11 Arora
  6. Hongbiao Carl Lekaye
    31 Lekaye
  7. Jason A Koutcher
    268 Koutcher
  8. Brett Stewart Carver
    133 Carver
  9. Howard Scher
    1081 Scher