Activated 3′,5′-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line

被引:100
作者
Cox, ME
Deeble, PD
Bissonette, EA
Parsons, SJ
机构
[1] Univ Virginia, Hlth Sci Ctr, Dept Microbiol, Sch Med, Charlottesville, VA 22908 USA
[2] Univ Virginia, Sch Med, Ctr Canc, Charlottesville, VA 22908 USA
[3] Univ Virginia Hlth Syst, Dept Hlth Evaluat Sci, Charlottesville, VA 22908 USA
关键词
D O I
10.1074/jbc.275.18.13812
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neuroendocrine (NE) differentiation within prostate tumors is proposed to be a contributing factor in disease progression. However, the cellular origin and molecular mechanism controlling differentiation of prostatic NE cells are unresolved. The prostate tumor cell line, LNCaP, can reversibly acquire many NE characteristics in response to treatment with beta-adrenergic receptor agonists and activators of adenylate cyclase. In this study, we demonstrate that these treatments induce protein kinase A (PKA) activation in LNCaP cells and that ectopic expression of a constitutively activated form of the PKA catalytic subunit, CI alpha, results in acquisition of NE characteristics, including the extension of neuritic processes, cessation of mitotic activity, and production of neuron-specific enolase. Forskolin-, epinephrine-, and isoproterenol-dependent NE differentiation of LNCaP cells was significantly inhibited by expressing a dominant negative mutant of the PKA regulatory subunit, RI alpha, These results demonstrate that prostatic NE differentiation in response to these agents depends on PKA activation, and this signaling pathway may provide a therapeutic target for treating advanced forms of prostate cancer.
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页码:13812 / 13818
页数:7
相关论文
共 40 条
[1]   PARTIAL CHARACTERIZATION OF A THYROID-STIMULATING HORMONE-LIKE PEPTIDE IN NEURO-ENDOCRINE CELLS OF THE HUMAN-PROSTATE GLAND [J].
ABRAHAMSSON, PA ;
LILJA, H .
PROSTATE, 1989, 14 (01) :71-81
[2]   TERMINAL NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CARCINOMA-CELLS IN RESPONSE TO INCREASED INTRACELLULAR CYCLIC-AMP [J].
BANG, YJ ;
PIRNIA, F ;
FANG, WG ;
KANG, WK ;
SARTOR, O ;
WHITESELL, L ;
HA, MJ ;
TSOKOS, M ;
SHEAHAN, MD ;
NGUYEN, P ;
NIKLINSKI, WT ;
MYERS, CE ;
TREPEL, JB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (12) :5330-5334
[3]  
BOLOGNA M, 1989, CANCER, V63, P1714
[4]  
Bonkhoff H, 1998, PROSTATE, P18
[5]  
Bonkhoff H, 1996, PROSTATE, V28, P98
[6]   RELATION OF ENDOCRINE-PARACRINE CELLS TO CELL-PROLIFERATION IN NORMAL, HYPERPLASTIC, AND NEOPLASTIC HUMAN PROSTATE [J].
BONKHOFF, H ;
WERNERT, N ;
DHOM, G ;
REMBERGER, K .
PROSTATE, 1991, 19 (02) :91-98
[7]   C-SRC REGULATES THE SIMULTANEOUS REARRANGEMENT OF ACTIN CYTOSKELETON, P190RHOGAP, AND P120RASGAP FOLLOWING EPIDERMAL GROWTH-FACTOR STIMULATION [J].
CHANG, JH ;
GILL, S ;
SETTLEMAN, J ;
PARSONS, SJ .
JOURNAL OF CELL BIOLOGY, 1995, 130 (02) :355-368
[8]  
CLEGG CH, 1987, J BIOL CHEM, V262, P13111
[9]   NEUROENDOCRINE CELLS - A NEW PROGNOSTIC PARAMETER IN PROSTATE-CANCER [J].
COHEN, RJ ;
GLEZERSON, G ;
HAFFEJEE, Z .
BRITISH JOURNAL OF UROLOGY, 1991, 68 (03) :258-262
[10]  
Cox ME, 1999, CANCER RES, V59, P3821