help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Murillo, H.
Right arrow Articles by Tindall, D. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Murillo, H.
Right arrow Articles by Tindall, D. J.
Endocrinology Vol. 142, No. 11 4795-4805
Copyright © 2001 by The Endocrine Society

ARTICLES

Role of PI3K Signaling in Survival and Progression of LNCaP Prostate Cancer Cells to the Androgen Refractory State

Horacio Murillo1, Haojie Huang1, Lucy J. Schmidt, David I. Smith and Donald J. Tindall

Departments of Molecular Pharmacology and Experimental Therapeutics (H.M.), Urology Research (H.M.,, H.H., L.J.S., D.J.T.), Laboratory Medicine and Pathology (D.I.S.), and Biochemistry and Molecular Biology (D.J.T.), Mayo Clinic and Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: D. J. Tindall, Ph.D., Department of Urology Research, Guggenheim 1701, Mayo Foundation, 200 First Street SW, Rochester, Minnesota 55905. E-mail: tindall.donald{at}mayo.edu

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 G1 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 p27kip1 protein levels, whereas PI3K and Akt activity remained elevated. At this stage, PI3K inhibition rapidly triggered accumulation of p27kip1, cell cycle arrest, and cell death. PI3K modulated p27kip1 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.




This article has been cited by other articles:


Home page
 Cancer Res.Home page
W. Zhang, J. Zhu, C. L. Efferson, C. Ware, J. Tammam, M. Angagaw, J. Laskey, K. A. Bettano, S. Kasibhatla, J. F. Reilly, et al.
Inhibition of Tumor Growth Progression by Antiandrogens and mTOR Inhibitor in a Pten-Deficient Mouse Model of Prostate Cancer
Cancer Res., September 15, 2009; 69(18): 7466 - 7472.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. R. Epis, K. M. Giles, A. Barker, T. S. Kendrick, and P. J. Leedman
miR-331-3p Regulates ERBB-2 Expression and Androgen Receptor Signaling in Prostate Cancer
J. Biol. Chem., September 11, 2009; 284(37): 24696 - 24704.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
H. V. Heemers, K. M. Regan, L. J. Schmidt, S. K. Anderson, K. V. Ballman, and D. J. Tindall
Androgen Modulation of Coregulator Expression in Prostate Cancer Cells
Mol. Endocrinol., April 1, 2009; 23(4): 572 - 583.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
W.-C. Huang, J. J. Havel, H. E. Zhau, W. P. Qian, H.-W. Lue, C.-Y. Chu, T. Nomura, and L. W.K. Chung
{beta}2-Microglobulin Signaling Blockade Inhibited Androgen Receptor Axis and Caused Apoptosis in Human Prostate Cancer Cells
Clin. Cancer Res., September 1, 2008; 14(17): 5341 - 5347.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Liu, J. Q. Mo, Q. Hu, G. Boivin, L. Levin, S. Lu, D. Yang, Z. Dong, and S. Lu
Targeted Overexpression of Vav3 Oncogene in Prostatic Epithelium Induces Nonbacterial Prostatitis and Prostate Cancer
Cancer Res., August 1, 2008; 68(15): 6396 - 6406.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
C.-L. Hsieh, C. Cai, A. Giwa, A. Bivins, S.-Y. Chen, D. Sabry, K. Govardhan, and L. Shemshedini
Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells
J. Mol. Endocrinol., July 1, 2008; 41(1): 13 - 23.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. Hara, H. Miyazaki, A. Lee, C. P. Tran, and R. E. Reiter
Androgen Receptor and Invasion in Prostate Cancer
Cancer Res., February 15, 2008; 68(4): 1128 - 1135.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
A. Schayowitz, G. Sabnis, V. C.O. Njar, and A. M.H. Brodie
Synergistic effect of a novel antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro
Mol. Cancer Ther., January 1, 2008; 7(1): 121 - 132.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
P. J. Gray Jr., M. A. Stevenson, and S. K. Calderwood
Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells
Cancer Res., December 15, 2007; 67(24): 11942 - 11950.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. V. Heemers, K. M. Regan, S. M. Dehm, and D. J. Tindall
Androgen Induction of the Androgen Receptor Coactivator Four and a Half LIM Domain Protein-2: Evidence for a Role for Serum Response Factor in Prostate Cancer
Cancer Res., November 1, 2007; 67(21): 10592 - 10599.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
R. M. Adam, N. K. Mukhopadhyay, J. Kim, D. Di Vizio, B. Cinar, K. Boucher, K. R. Solomon, and M. R. Freeman
Cholesterol Sensitivity of Endogenous and Myristoylated Akt
Cancer Res., July 1, 2007; 67(13): 6238 - 6246.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. V. Heemers, T. J. Sebo, J. D. Debes, K. M. Regan, K. A. Raclaw, L. M. Murphy, A. Hobisch, Z. Culig, and D. J. Tindall
Androgen Deprivation Increases p300 Expression in Prostate Cancer Cells
Cancer Res., April 1, 2007; 67(7): 3422 - 3430.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
B. Li, A. Sun, H. Youn, Y. Hong, P. F. Terranova, J.B. Thrasher, P. Xu, and D. Spencer
Conditional Akt activation promotes androgen-independent progression of prostate cancer
Carcinogenesis, March 1, 2007; 28(3): 572 - 583.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Wu and J. Huang
Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer
J. Biol. Chem., February 9, 2007; 282(6): 3571 - 3583.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
T. Inoue, T. Yoshida, Y. Shimizu, T. Kobayashi, T. Yamasaki, Y. Toda, T. Segawa, T. Kamoto, E. Nakamura, and O. Ogawa
Requirement of Androgen-Dependent Activation of Protein Kinase C{zeta} for Androgen-Dependent Cell Proliferation in LNCaP Cells and Its Roles in Transition to Androgen-Independent Cells
Mol. Endocrinol., December 1, 2006; 20(12): 3053 - 3069.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. M.R. Bhuiyan, Y. Li, S. Banerjee, F. Ahmed, Z. Wang, S. Ali, and F. H. Sarkar
Down-regulation of Androgen Receptor by 3,3'-Diindolylmethane Contributes to Inhibition of Cell Proliferation and Induction of Apoptosis in Both Hormone-Sensitive LNCaP and Insensitive C4-2B Prostate Cancer Cells.
Cancer Res., October 15, 2006; 66(20): 10064 - 10072.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
H. V. Heemers, G. Verhoeven, and J. V. Swinnen
Androgen Activation of the Sterol Regulatory Element-Binding Protein Pathway: Current Insights
Mol. Endocrinol., October 1, 2006; 20(10): 2265 - 2277.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
Z. Dong, Y. Liu, S. Lu, A. Wang, K. Lee, L.-H. Wang, M. Revelo, and S. Lu
Vav3 Oncogene Is Overexpressed and Regulates Cell Growth and Androgen Receptor Activity in Human Prostate Cancer
Mol. Endocrinol., October 1, 2006; 20(10): 2315 - 2325.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. Bertram, J. W. Peacock, C. Tan, A. L-F. Mui, S. W. Chung, M. E. Gleave, S. Dedhar, M. E. Cox, and C. J. Ong
Inhibition of the Phosphatidylinositol 3'-Kinase Pathway Promotes Autocrine Fas-Induced Death of Phosphatase and Tensin Homologue-Deficient Prostate Cancer Cells.
Cancer Res., May 1, 2006; 66(9): 4781 - 4788.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
L. S. Lyons and K. L. Burnstein
Vav3, a Rho GTPase Guanine Nucleotide Exchange Factor, Increases during Progression to Androgen Independence in Prostate Cancer Cells and Potentiates Androgen Receptor Transcriptional Activity
Mol. Endocrinol., May 1, 2006; 20(5): 1061 - 1072.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
L. A. Gomez, A. de las Pozas, and C. Perez-Stable
Sequential combination of flavopiridol and docetaxel reduces the levels of X-linked inhibitor of apoptosis and AKT proteins and stimulates apoptosis in human LNCaP prostate cancer cells
Mol. Cancer Ther., May 1, 2006; 5(5): 1216 - 1226.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
M. H. Aziz, M. Nihal, V. X. Fu, D. F. Jarrard, and N. Ahmad
Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/Akt pathway and Bcl-2 family proteins
Mol. Cancer Ther., May 1, 2006; 5(5): 1335 - 1341.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Jiang, H.-J. Lee, G.-x. Li, J. Guo, B. Malewicz, Y. Zhao, E.-O. Lee, H.-J. Lee, J.-H. Lee, M.-S. Kim, et al.
Potent Antiandrogen and Androgen Receptor Activities of an Angelica gigas-Containing Herbal Formulation: Identification of Decursin as a Novel and Active Compound with Implications for Prevention and Treatment of Prostate Cancer
Cancer Res., January 1, 2006; 66(1): 453 - 463.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. Jelovac, G. Sabnis, B. J. Long, L. Macedo, O. G. Goloubeva, and A. M.H. Brodie
Activation of Mitogen-Activated Protein Kinase in Xenografts and Cells during Prolonged Treatment with Aromatase Inhibitor Letrozole
Cancer Res., June 15, 2005; 65(12): 5380 - 5389.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
Z Culig, H Steiner, G Bartsch, and A Hobisch
Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours
Endocr. Relat. Cancer, June 1, 2005; 12(2): 229 - 244.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
P. M Ghosh, S. N Malik, R. G Bedolla, Y. Wang, M. Mikhailova, T. J Prihoda, D. A Troyer, and J. I Kreisberg
Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation
Endocr. Relat. Cancer, March 1, 2005; 12(1): 119 - 134.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
J. K Oosterhoff, J A. Grootegoed, and L. J Blok
Expression profiling of androgen-dependent and -independent LNCaP cells: EGF versus androgen signalling
Endocr. Relat. Cancer, March 1, 2005; 12(1): 135 - 148.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
R. L. Lynch, B. W. Konicek, A. M. McNulty, K. R. Hanna, J. E. Lewis, B. L. Neubauer, and J. R. Graff
The Progression of LNCaP Human Prostate Cancer Cells to Androgen Independence Involves Decreased FOXO3a Expression and Reduced p27KIP1 Promoter Transactivation
Mol. Cancer Res., March 1, 2005; 3(3): 163 - 169.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. T. Lee Jr., L. S. Steelman, and J. A. McCubrey
Phosphatidylinositol 3'-Kinase Activation Leads to Multidrug Resistance Protein-1 Expression and Subsequent Chemoresistance in Advanced Prostate Cancer Cells
Cancer Res., November 15, 2004; 64(22): 8397 - 8404.
[Abstract] [Full Text] [PDF]

Home page
 J AndrolHome page
L. J. Schmidt, H. Murillo, and D. J. Tindall
Gene Expression in Prostate Cancer Cells Treated With the Dual 5 Alpha-Reductase Inhibitor Dutasteride
J Androl, November 1, 2004; 25(6): 944 - 953.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. I. Kreisberg, S. N. Malik, T. J. Prihoda, R. G. Bedolla, D. A. Troyer, S. Kreisberg, and P. M. Ghosh
Phosphorylation of Akt (Ser473) is an Excellent Predictor of Poor Clinical Outcome in Prostate Cancer
Cancer Res., August 1, 2004; 64(15): 5232 - 5236.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
X. Liao, J. B. Thrasher, J. Holzbeierlein, S. Stanley, and B. Li
Glycogen Synthase Kinase-3{beta} Activity Is Required for Androgen-Stimulated Gene Expression in Prostate Cancer
Endocrinology, June 1, 2004; 145(6): 2941 - 2949.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Huang, D. C. Muddiman, and D. J. Tindall
Androgens Negatively Regulate Forkhead Transcription Factor FKHR (FOXO1) through a Proteolytic Mechanism in Prostate Cancer Cells
J. Biol. Chem., April 2, 2004; 279(14): 13866 - 13877.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
J. M. Ueland, J. Gwira, Z.-X. Liu, and L. G. Cantley
The chemokine KC regulates HGF-stimulated epithelial cell morphogenesis
Am J Physiol Renal Physiol, March 1, 2004; 286(3): F581 - F589.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
H.-K. Lin, Y.-C. Hu, L. Yang, S. Altuwaijri, Y.-T. Chen, H.-Y. Kang, and C. Chang
Suppression Versus Induction of Androgen Receptor Functions by the Phosphatidylinositol 3-Kinase/Akt Pathway in Prostate Cancer LNCaP Cells with Different Passage Numbers
J. Biol. Chem., December 19, 2003; 278(51): 50902 - 50907.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
L. Li, C. H. Ren, S. A. Tahir, C. Ren, and T. C. Thompson
Caveolin-1 Maintains Activated Akt in Prostate Cancer Cells through Scaffolding Domain Binding Site Interactions with and Inhibition of Serine/Threonine Protein Phosphatases PP1 and PP2A
Mol. Cell. Biol., December 15, 2003; 23(24): 9389 - 9404.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C.-C. Yang, H.-P. Lin, C.-S. Chen, Y.-T. Yang, P.-H. Tseng, V. M. Rangnekar, and C.-S. Chen
Bcl-xL Mediates a Survival Mechanism Independent of the Phosphoinositide 3-Kinase/Akt Pathway in Prostate Cancer Cells
J. Biol. Chem., July 3, 2003; 278(28): 25872 - 25878.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Yang, H.-K. Lin, S. Altuwaijri, S. Xie, L. Wang, and C. Chang
APPL Suppresses Androgen Receptor Transactivation via Potentiating Akt Activity
J. Biol. Chem., May 2, 2003; 278(19): 16820 - 16827.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. J. Nesslinger, X.-B. Shi, and R. W. deVere White
Androgen-independent Growth of LNCaP Prostate Cancer Cells Is Mediated by Gain-of-Function Mutant p53
Cancer Res., May 1, 2003; 63(9): 2228 - 2233.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2001 by The Endocrine Society