Abstract
The neuroendocrine (NE) cells represent the third cell population in the normal prostate. Results of several clinical studies strongly indicate that the NE cell population is greatly increased in prostate carcinomas during androgen ablation therapy that correlates with hormone-refractory growth and poor prognosis. However, the mechanism of NE cell enrichment in prostate carcinoma remains an enigma. We investigated the molecular mechanism by which androgen-sensitive C-33 LNCaP human prostate cancer cells become NE-like cells in an androgen-reduced environment, mimicking clinical phenomenon. In the androgen-depleted condition, androgen-sensitive C-33 LNCaP cells gradually acquired the NE-like morphology and expressed an increased level of neuron-specific enolase (NSE), a classical marker of neuronal cells. Several NE-like subclone cells were established. Biochemical characterizations of these subclone cells showed that receptor-type protein-tyrosine phosphatase alpha (RPTPα) is elevated and ERK is constitutively activated, several folds higher than that in parental cells. In androgen-depleted condition, PD98059, an MEK inhibitor, could efficiently block not only the activation of ERK, but also the acquisition of the NE-like morphology and the elevation of NSE in C-33 LNCaP cells. In RPTPα cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE was elevated. In those cells in the presence of PD98059, the ERK activation and NSE elevation were abolished, following a dose–response fashion. Additionally, in constitutively active MEK mutant cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE level was elevated, and cells obtained the NE-like phenotype. Our data collectively indicated that RPTPα signaling via ERK is involved in the NE transdifferentiation of androgen-sensitive C-33 LNCaP human prostate cancer cells in the androgen-depleted condition.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- NE:
-
neuroendocrine
- NSE:
-
neuron-specific enolase
- cAMP:
-
adenosine 3′,5′-cyclic monophosphate
- db-cAMP:
-
dibutyrate cAMP
- PKA:
-
protein kinase A
- PI3K:
-
phosphatidylinositol 3-kinase
- IL:
-
interleukin
- ERK:
-
extracellular signal-regulated kinase
- MEK:
-
ERK kinase
- MAPK:
-
mitogen-activated protein kinase
- MKP:
-
ERK/MAPK phosphatase
- NGF:
-
nerve growth factor
- HA:
-
hemagglutinin
- FBS:
-
fetal bovine serum
- SR-FBS:
-
steroid-reduced FBS
- ECL:
-
enhanced chemiluminescence
- GFP:
-
green fluorescent protein
- PTP:
-
protein tyrosine phosphatase
- RPTPα:
-
receptor protein tyrosine phosphatase alpha
- DHT:
-
5α-dihydrotestosterone
- Ab:
-
antibody
References
Abrahamsson PA . (1999a). Prostate, 39, 135–148.
Abrahamsson PA . (1999b). Endocr. Relat. Cancer, 6, 503–519.
Abrahamsson PA and Lilja H . (1989). Prostate, 14, 71–81.
Almagro UA, Tieu TM, Remeniuk E, Kueck B and Strumpf K . (1986). Arch. Pathol. Lab. Med., 110, 916–919.
Bang YJ, Pirnia F, Fang WG, Kang WK, Sartor O, Whitesell L, Ha MJ, Tsokos M, Sheahan MD and Nguyen P . (1994). Proc. Natl. Acad. Sci. USA, 91, 5330–5334.
Bennett AM and Tonks NK . (1997). Science, 278, 1288–1291.
Bologna M, Festuccia C, Muzi P, Biordi L and Ciomei M . (1989). Cancer, 63, 1714–1720.
Bonkhoff H . (1998). Prostate Suppl., 8, 18–22.
Bonkhoff H and Remberger K . (1996). Prostate, 28, 98–106.
Bonkhoff H, Wernert N, Dhom G and Remberger K . (1991). Prostate, 19, 91–98.
Burchardt T, Burchardt M, Chen MW, Cao Y, de_la_Taille A, Shabsigh A, Hayek O, Dorai T and Buttyan R . (1999). J. Urol., 162, 1800–1805.
Chen T, Cho RW, Stork PJ and Weber MJ . (1999). Cancer Res., 59, 213–218.
Cockett AT, di Sant'Agnese PA, Gopinath P, Schoen SR and Abrahamsson PA . (1993). Urology, 42, 512–519.
Cohen RJ, Glezerson G and Haffejee Z . (1991). Br. J. Urol., 68, 258–262.
Cowley S, Paterson H, Kemp P and Marshall CJ . (1994). Cell, 77, 841–852.
Cox ME, Deeble PD, Bissonette EA and Parsons SJ . (2000). J. Biol.Chem., 275, 13812–13818.
Cox ME, Deeble PD, Lakhani S and Parsons SJ . (1999). Cancer Res., 59, 3821–3830.
Deeble PD, Murphy DJ, Parsons SJ and Cox ME . (2001). Mol. Cell. Biol., 21, 8471–8482.
den Hertog J and Hunter T . (1996). EMBO J., 15, 3016–3027.
den Hertog J, Pals CE, Peppelenbosch MP, Tertoolen LG, de Laat SW and Kruijer W . (1993). EMBO J., 12, 3789–3798.
den Hertog J, Tracy S and Hunter T . (1994). EMBO J., 13, 3020–3032.
di Sant'Agnese PA . (1998a). Prostate Suppl., 8, 74–79.
di Sant'Agnese PA . (1998b). Urology, 51, 121–124.
di Sant'Agnese PA and Cockett AT . (1996). Cancer, 78, 357–361.
Diaz M, Abdul M and Hoosein N . (1998). Prostate Suppl., 8, 32–36.
Ferrell Jr JE . (1996). Curr. Top. Dev. Biol., 33, 1–60.
Fronsdal K, Engedal N and Saatcioglu F . (2000). Prostate, 43, 111–117.
Fukuda M, Gotoh Y, Tachibana T, Dell K, Hattori S, Yoneda Y and Nishida E . (1995). Oncogene, 11, 239–244.
Gioeli D, Mandell JW, Petroni GR, Frierson Jr HF and Weber MJ . (1999). Cancer Res., 59, 279–284.
Gkonos PJ, Krongrad A and Roos BA . (1995). Urol. Res., 23, 81–87.
Gredinger E, Gerber AN, Tamir Y, Tapscott SJ and Bengal E . (1998). J. Biol. Chem., 273, 10436–10444.
Greenlee RT, Hill-Harmon MB, Murray T and Thun M . (2001). CA Cancer J. Clin., 51, 15–36.
Hu X, Moscinski LC, Valkov NI, Fisher AB, Hill BJ and Zuckerman KS . (2000). Cell Growth Differ., 11, 191–200.
Ihara S, Nakajima K, Fukada T, Hibi M, Nagata S, Hirano T and Fukui Y . (1997). EMBO J., 16, 5345–5352.
Iwamura M, Abrahamsson PA, Foss KA, Wu G, Cockett AT and Deftos LJ . (1994). Urology, 43, 675–679.
Iwasaki S, Hattori A, Sato M, Tsujimoto M and Kohno M . (1996). J. Biol. Chem., 271, 17360–17365.
Jacob KK, Sap J and Stanley FM . (1998). J. Biol. Chem., 273, 4800–4809.
Jiang G, den Hertog J, Su J, Noel J, Sap J and Hunter T . (1999). Nature, 401, 606–610.
Jongsma J, Oomen MH, Noordzij MA, Van Weerden WM, Martens GJ, van der Kwast TH, Schroder FH and van Steenbrugge GJ . (2000). Cancer Res., 60, 741–748.
Kim J, Adam RM and Freeman MR . (2002). Cancer Res, 62, 1549–1554.
Lammers R, Moller NP and Ullrich A . (1997). FEBS Lett., 404, 37–40.
Lee LF, Guan J, Qiu Y and Kung HJ . (2001). Mol. Cell. Biol., 21, 8385–8397.
Lee MS, Igawa T, Yuan TC, Zhang XQ, Lin FF and Lin MF . (2003). Oncogene, 22, 781–796.
Lewis TS, Shapiro PS and Ahn NG . (1998). Adv. Cancer Res., 74, 49–139.
Lin MF and Clinton GM . (1986). Biochem. J., 235, 351–357.
Lin MF, DaVolio J and Garcia-Arenas R . (1992). Cancer Res., 52, 4600–4607.
Lin MF, Lee MS, Garcia-Arenas R and Lin FF . (2000). Cell. Biol. Int., 24, 681–689.
Lin MF, Lee MS, Zhou XW, Andressen JC, Meng TC, Johansson SL, West WW, Taylor RJ, Anderson JR and Lin FF . (2001). J. Urol., 166, 1943–1950.
Lin MF, Meng TC, Rao PS, Chang C, Schonthal AH and Lin FF . (1998). J. Biol. Chem., 273, 5939–5947.
Marshall CJ . (1995). Cell, 80, 179–185.
Meng TC and Lin MF . (1998). J. Biol. Chem., 273, 22096–22104.
Meng TC, Lee MS and Lin MF . (2000). Oncogene, 19, 2664–2677.
Mori S, Murakami-Mori K and Bonavida B . (1999). Biochem. Biophys. Res. Commun., 257, 609–614.
Noordzij MA, van Weerden WM, de Ridder CM, van der Kwast TH, Schroder FH and van Steenbrugge GJ . (1996). Am. J. Pathol., 149, 859–871.
Pang L, Sawada T, Decker SJ and Saltiel AR . (1995). J. Biol. Chem., 270, 13585–13588.
Price DT, Rocca GD, Guo C, Ballo MS, Schwinn DA and Luttrell LM . (1999). J. Urol., 162, 1537–1542.
Qiu Y, Robinson D, Pretlow TG and Kung HJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 3644–3649.
Racke FK, Lewandowska K, Goueli S and Goldfarb AN . (1997). J. Biol. Chem., 272, 23366–23370.
Ruokonen M, Shan JD, Hedberg P, Patrikainen L and Vihko P . (1996). Biochem. Biophys. Res. Commun., 218, 794–796.
Schaeffer HJ and Weber MJ . (1999). Mol. Cell. Biol., 19, 2435–2444.
Seethalakshmi L, Mitra SP, Dobner PR, Menon M and Carraway RE . (1997). Prostate, 31, 183–192.
Seger R and Krebs EG . (1995). FASEB J., 9, 726–735.
Seuwen K and Pouyssegur J . (1990). Biochem. Pharmacol., 39, 985–990.
Shah GV, Rayford W, Noble MJ, Austenfeld M, Weigel J, Vamos S and Mebust WK . (1994). Endocrinology, 134, 596–602.
Shen R, Dorai T, Szaboles M, Katz AE, Olsson CA and Buttyan R . (1997). Urol. Oncol., 3, 67–75.
Su J, Muranjan M and Sap J . (1999). Curr. Biol., 9, 505–511.
Sundaram M and Han M . (1996). BioEssays, 18, 473–480.
Tarle M, Frkovic-Grazio S, Kraljic I and Kovacic K . (1994). Prostate, 24, 143–148.
Tetu B, Ro JY, Ayala AG, Johnson DE, Logothetis CJ and Ordonez NG . (1987). Cancer, 59, 1803–1809.
Theodorescu D, Broder SR, Boyd JC, Mills SE and Frierson Jr HF . (1997). Cancer, 80, 2109–2119.
Treisman R . (1996). Curr. Opin. Cell. Biol., 8, 205–215.
Tsai W, Morielli AD, Cachero TG and Peralta EG . (1999). EMBO J., 18, 109–118.
Umbhauer M, Marshall CJ, Mason CS, Old RW and Smith JC . (1995). Nature, 376, 58–62.
van Inzen WG, Peppelenbosch MP, van den Brand MW, Tertoolen LG and de Laat S . (1996). Brain Res. Dev. Brain Res., 91, 304–307.
Vossler MR, Yao H, York RD, Pan MG, Rim CS and Stork PJ . (1997). Cell, 89, 73–82.
Whalen AM, Galasinski SC, Shapiro PS, Nahreini TS and Ahn NG . (1997). Mol. Cell. Biol., 17, 1947–1958.
Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME . (1995). Science, 270, 1326–1331.
Yao H, York RD, Misra-Press A, Carr DW and Stork PJ . (1998). J. Biol. Chem., 273, 8240–8247.
Zelivianski S, Comeau D and Lin MF . (1998). Biochem. Biophys. Res. Commun., 245, 108–112.
Zelivianski S, Dean J, Madhavan D, Lin FF and Lin MF . (2000). Mol. Cell. Biochem., 208, 11–18.
Zelivianski S, Verni M, Moore C, Kondrikov D, Taylor R and Lin MF . (2001). Biochim. Biophys. Acta., 1539, 28–43.
Zeng L, D'Alessandri L, Kalousek MB, Vaughan L and Pallen CJ . (1999). J. Cell. Biol., 147, 707–714.
Zhang XQ, Lee MS, Zelivianski S and Lin MF . (2001). J. Biol. Chem., 276, 2544–2550.
Zheng XM and Pallen CJ . (1994). J. Biol. Chem., 269, 23302–23309.
Zheng XM, Resnick RJ and Shalloway D . (2000). EMBO J., 19, 964–978.
Zi X and Agarwal R . (1999). Proc. Natl. Acad. Sci. USA, 96, 7490–7495.
Acknowledgements
We thank Dr Tony Hunter at the Salk Institute for the murine RPTPα cDNA encoding the wild-type and the mutant proteins and its Ab, and Dr Parmender P Mehta at UNMC for providing Alexa 594-conjugated goat anti-mouse IgG. We also thank the fluorescent microscope core facility at the Department of Surgery, the confocal microscope core facility at the Department of Biochemistry and Molecular Biology, and the lab colleagues for their helpful suggestions and discussions. This work was supported in part by NCI CA72274 and CA88184 from the National Institutes of Health, Nebraska Department of Health/Eppley Cancer Center LB595, and the UNMC College of Medicine Research Grant Award.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, XQ., Kondrikov, D., Yuan, TC. et al. Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. Oncogene 22, 6704–6716 (2003). https://doi.org/10.1038/sj.onc.1206764
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206764
Keywords
This article is cited by
-
AR antagonists develop drug resistance through TOMM20 autophagic degradation-promoted transformation to neuroendocrine prostate cancer
Journal of Experimental & Clinical Cancer Research (2023)
-
Neuropilin-2 promotes lineage plasticity and progression to neuroendocrine prostate cancer
Oncogene (2022)
-
TCF7L1 regulates cytokine response and neuroendocrine differentiation of prostate cancer
Oncogenesis (2021)
-
Loss and revival of androgen receptor signaling in advanced prostate cancer
Oncogene (2021)
-
Cellular rewiring in lethal prostate cancer: the architect of drug resistance
Nature Reviews Urology (2020)