Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state

被引:235
作者
Murillo, H
Huang, HJ
Schmidt, LJ
Smith, DI
Tindall, DJ
机构
[1] Mayo Clin & Mayo Fdn, Dept Urol Res, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Dept Mol Pharmacol, Rochester, MN 55905 USA
[3] Mayo Clin & Mayo Fdn, Dept Expt Therapeut, Rochester, MN 55905 USA
[4] Mayo Clin & Mayo Fdn, Lab Med & Pathol, Rochester, MN 55905 USA
[5] Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Rochester, MN 55905 USA
关键词
D O I
10.1210/en.142.11.4795
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The mechanisms by which prostate cancer (PCa) cells progress to a hormone refractory state are poorly understood. The progression process under androgen ablation conditions involves the survival of at least a portion of malignant cells and their eventual proliferation in an androgen-independent manner. The goal of this study was to investigate the role of PI3K signaling in such a progression. Using an in vitro model of androgen ablation, we show that after removal of androgen support, the human PCa cell line LNCaP initially arrested in G, and trans-differentiated into neuroendocrine-like cells that eventually resumed androgen-independent proliferation. Both acute and chronic androgen ablation resulted in an increase in basal levels of PI3K and Akt activity, which were sustained throughout the progression process. Under these conditions, inhibition of PI3K, pharmacologically or with ectopic expression of PTEN, arrested cell proliferation and blocked progression to the androgen-independent state. In contrast, LNCaP cells in the presence of androgens were marginally sensitive to PI3K inhibition. During the chronic stage of androgen deprivation, androgen-independent proliferation correlated with diminished p27(kip1) protein levels, whereas PI3K and Akt activity remained elevated. At this stage, PI3K inhibition rapidly triggered accumulation of p27(kip1), cell cycle arrest, and cell death. PI3K modulated p27(kip1) levels at least in part by regulating its rate of degradation. Taken together, these data show that androgen ablation alone can increase PI3K-Akt activation, which supports survival after acute androgen ablation and proliferation during chronic androgen deprivation. Successful progression to the androgen-independent state in the LNCaP cell line model requires intact PI3K signaling.
引用
收藏
页码:4795 / 4805
页数:11
相关论文
共 62 条
[31]   Molecular mechanisms of androgen-independent growth of human prostate cancer LNCaP-AI cells [J].
Lu, S ;
Tsai, SY ;
Tsai, MJ .
ENDOCRINOLOGY, 1999, 140 (11) :5054-5059
[32]   Role of p27 in prostate carcinogenesis [J].
Macri, E ;
Loda, M .
CANCER AND METASTASIS REVIEWS, 1998, 17 (04) :337-344
[33]   PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27KIP1 through the ubiquitin E3 ligase SCFSKP2 [J].
Mamillapalli, R ;
Gavrilova, N ;
Mihaylova, VT ;
Tsvetkov, LM ;
Wu, H ;
Zhang, H ;
Sun, H .
CURRENT BIOLOGY, 2001, 11 (04) :263-267
[34]   AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1 [J].
Medema, RH ;
Kops, GJPL ;
Bos, JL ;
Burgering, BMT .
NATURE, 2000, 404 (6779) :782-787
[35]   Synergistic effects of neurotensin and β-adrenergic agonist on 3′,5′-cyclic adenosine monophosphate accumulation and DNA synthesis in prostate cancer PC3 cells [J].
Mitra, SP ;
Carraway, RE .
BIOCHEMICAL PHARMACOLOGY, 1999, 57 (12) :1391-1397
[36]   HORMONAL-REGULATION OF PROSTATE-SPECIFIC ANTIGEN (PSA) GLYCOPROTEIN IN THE HUMAN PROSTATIC ADENOCARCINOMA CELL-LINE, LNCAP [J].
MONTGOMERY, BT ;
YOUNG, CYF ;
BILHARTZ, DL ;
ANDREWS, PE ;
PRESCOTT, JL ;
THOMPSON, NF ;
TINDALL, DJ .
PROSTATE, 1992, 21 (01) :63-73
[37]   Changes in cyclin dependent kinase inhibitors p21 and p27 during the castration induced regression of the CWR22 model of prostatic adenocarcinoma [J].
Myers, RB ;
Oelschlager, DK ;
Coan, PN ;
Frost, AR ;
Weiss, HL ;
Manne, U ;
Pretlow, TG ;
Grizzle, WE .
JOURNAL OF UROLOGY, 1999, 161 (03) :945-949
[38]   Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN [J].
Nakamura, N ;
Ramaswamy, S ;
Vazquez, F ;
Signoretti, S ;
Loda, M ;
Sellers, WR .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (23) :8969-8982
[39]   Small bioactive peptides and cell surface peptidases in androgen-independent prostate cancer [J].
Nelson, JB ;
Carducci, MA .
CANCER INVESTIGATION, 2000, 18 (01) :87-96
[40]   Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression [J].
Papandreou, CN ;
Usmani, B ;
Geng, YP ;
Bogenrieder, T ;
Freeman, R ;
Wilk, S ;
Finstad, CL ;
Reuter, VE ;
Powell, CT ;
Scheinberg, D ;
Magill, C ;
Scher, HI ;
Albino, AP ;
Nanus, DM .
NATURE MEDICINE, 1998, 4 (01) :50-57