Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27(Kip1) expression

J. R. Graff, B. W. Konicek, A. M. McNulty, Z. Wang, K. Houck, S. Allen, J. D. Paul, A. Hbaiu, R. G. Goode, George Sandusky, R. L. Vessella, B. L. Neubauer

Research output: Contribution to journalArticle

324 Citations (Scopus)

Abstract

The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27(Kip1) cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27(Kip1). To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p27(Kip1) expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27(Kip1) expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.

Original languageEnglish (US)
Pages (from-to)24500-24505
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number32
DOIs
StatePublished - Aug 11 2000
Externally publishedYes

Fingerprint

Tumors
Prostate
Prostatic Neoplasms
Androgens
Phosphorylation
Cells
Growth
Heterografts
Neoplasms
Chemical activation
Proto-Oncogene Proteins c-akt
Transcription
Prostate-Specific Antigen
Phosphotransferases
Genes
Tumor Suppressor Genes
Cell Cycle
Cell Line
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27(Kip1) expression. / Graff, J. R.; Konicek, B. W.; McNulty, A. M.; Wang, Z.; Houck, K.; Allen, S.; Paul, J. D.; Hbaiu, A.; Goode, R. G.; Sandusky, George; Vessella, R. L.; Neubauer, B. L.

In: Journal of Biological Chemistry, Vol. 275, No. 32, 11.08.2000, p. 24500-24505.

Research output: Contribution to journalArticle

Graff, JR, Konicek, BW, McNulty, AM, Wang, Z, Houck, K, Allen, S, Paul, JD, Hbaiu, A, Goode, RG, Sandusky, G, Vessella, RL & Neubauer, BL 2000, 'Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27(Kip1) expression', Journal of Biological Chemistry, vol. 275, no. 32, pp. 24500-24505. https://doi.org/10.1074/jbc.M003145200
Graff, J. R. ; Konicek, B. W. ; McNulty, A. M. ; Wang, Z. ; Houck, K. ; Allen, S. ; Paul, J. D. ; Hbaiu, A. ; Goode, R. G. ; Sandusky, George ; Vessella, R. L. ; Neubauer, B. L. / Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27(Kip1) expression. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 32. pp. 24500-24505.
@article{e5152078099241888985274acabfef0b,
title = "Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27(Kip1) expression",
abstract = "The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27(Kip1) cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27(Kip1). To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p27(Kip1) expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27(Kip1) expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.",
author = "Graff, {J. R.} and Konicek, {B. W.} and McNulty, {A. M.} and Z. Wang and K. Houck and S. Allen and Paul, {J. D.} and A. Hbaiu and Goode, {R. G.} and George Sandusky and Vessella, {R. L.} and Neubauer, {B. L.}",
year = "2000",
month = "8",
day = "11",
doi = "10.1074/jbc.M003145200",
language = "English (US)",
volume = "275",
pages = "24500--24505",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "32",

}

TY - JOUR

T1 - Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27(Kip1) expression

AU - Graff, J. R.

AU - Konicek, B. W.

AU - McNulty, A. M.

AU - Wang, Z.

AU - Houck, K.

AU - Allen, S.

AU - Paul, J. D.

AU - Hbaiu, A.

AU - Goode, R. G.

AU - Sandusky, George

AU - Vessella, R. L.

AU - Neubauer, B. L.

PY - 2000/8/11

Y1 - 2000/8/11

N2 - The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27(Kip1) cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27(Kip1). To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p27(Kip1) expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27(Kip1) expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.

AB - The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27(Kip1) cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27(Kip1). To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p27(Kip1) expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27(Kip1) expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.

UR - http://www.scopus.com/inward/record.url?scp=0034637524&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034637524&partnerID=8YFLogxK

U2 - 10.1074/jbc.M003145200

DO - 10.1074/jbc.M003145200

M3 - Article

VL - 275

SP - 24500

EP - 24505

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 32

ER -