ABSTRACT Androgen ablation therapy is eventually followed by a more metastatic and androgen-refractory stage of prostate cancer. The detailed molecular mechanism of this gradual transition

is not clearly understood. Recent reports correlate the high abundance of vascular endothelial growth factor-C (VEGF-C) to the lymph node metastasis seen in human prostate cancer (Tsurusaki

_et al._, 1999). In this study, we report that androgen ablation in LNCaP cells augment the transcriptional upregulation of VEGF-C and the downregulation of the IGF-IR pathway, due to

androgen withdrawal, is a potential mechanism for this observed VEGF-C transcription. Forkhead transcription factor FOXO-1, activated by SIRT-1, was identified as the downstream molecule

ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 50 print issues and online access $259.00 per year only $5.18 per issue Learn more Buy this article *

Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn

about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ABERRANT ANDROGEN ACTION IN PROSTATIC PROGENITOR CELLS INDUCES ONCOGENESIS

AND TUMOR DEVELOPMENT THROUGH IGF1 AND WNT AXES Article Open access 28 July 2022 THE NATURAL COMPOUND ATRARIC ACID SUPPRESSES ANDROGEN-REGULATED NEO-ANGIOGENESIS OF CASTRATION-RESISTANT

PROSTATE CANCER THROUGH ANGIOPOIETIN 2 Article Open access 05 May 2022 INTERACTIONS BETWEEN ANDROGEN AND IGF1 AXES IN PROSTATE TUMORIGENESIS Article 07 October 2024 REFERENCES * Achen MG,

Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K and Stacker SA . (1998). _Proc. Natl. Acad. Sci. USA_, 95, 548–553. * Achen MG, Williams RA, Baldwin ME, Lai P, Roufail S, Alitalo

K and Stacker SA . (2002). _Growth Factors_, 20, 99–107. * Araki T, Sasaki Y and Milbrandt J . (2004). _Science_, 305, 1010–1013. * Arnold JT, Le H, McFann KK and Blackman MR . (2005). _Am.

J. Physiol. Endocrinol. Metab._, 288, E573–E584. * Baron S, Manin M, Beaudoin C Leotoing L, Communal Y, Veyssiere G and Morel L . (2004). _J. Biol. Chem._, 279, 14579–14586. * Borkhardt A,

Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J, Henn T and Lampert F . (1997). _Oncogene_, 14, 195–202. * Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H,

Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MR Gygi SP, Sinclair DA, Alt FW and Greenberg ME . (2004). _Science_, 303, 2011–2015. * Carmeliet P . (2000). _Nat. Med._, 6,

389–395. taf/DynaPage.taf?file=/nm/journal/v6/n4/full/nm0400_389.htmltaf/DynaPage.taf?file=/nm/journal/v6/n4/abs/nm0400_389.html. * Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle

V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM,

Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D and Persico MG . (2001). _Nat. Med._, 7, 575–583. * Castoria G, Lombardi M, Barone MV, Bilancio A, Di Domenico M, De Falco A,

Varricchio L, Bottero D, Nanayakkara M, Migliaccio A and Auricchio F . (2004). _Steroids_, 69, 517–522. * Chilov D, Kukk E, Taira S, Jeltsch M, Kaukonen J, Palotie A, Joukov V and Alitalo K

. (1997). _J. Biol. Chem._, 272, 25176–25183. * Clarijs R, Schalkwijk L, Ruiter DJ and de Waal RM . (2001). _Invest. Ophthalmol. Vis. Sci._, 42, 1422–1428. * Cohen HY, Miller C Bitterman KJ,

Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R and Sinclair DA . (2004). _Science_, 305, 390–392. * Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M,

Nakajima T and Fukamizu A . (2004). _Proc. Natl. Acad. Sci. USA_, 101, 10042–10047. * Datta K, Nambudripad R, Pal S, Zhou M, Cohen HT and Mukhopadhyay D . (2000). _J. Biol. Chem._, 275,

20700–20706. * De Meyts P, Urso B, Christoffersen CT and Shymko RM . (1995). _Ann. NY Acad. Sci._, 766, 388–401. * de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N and Williams LT .

(1992). _Science_, 255, 989–991. * Denis L and Murphy GP . (1993). _Cancer_, 72, 3888–3895. * Dias S, Choy M, Alitalo K and Rafii S . (2002). _Blood_, 99, 2179–2184. * Dvorak HF . (2000).

_Semin. Perinatol._, 24, 75–78. * Dvorak HF, Brown LF, Detmar M and Dvorak AM . (1995). _Am. J. Pathol._, 146, 1029–1039. * Enholm B, Paavonen K, Ristimaki A, Kumar V, Gunji Y, Klefstrom J,

Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U and Alitalo K . (1997). _Oncogene_, 14, 2475–2483. * Epstein JI, Partin AW, Sauvageot J and Walsh PC . (1996). _Am. J. Surg. Pathol._,

20, 286–292. * Ferrara N . (2001). _Am. J. Physiol. Cell Physiol._, 280, C1358–66. * Folkman J . (1971). _N. Engl. J. Med._, 285, 1182–1186. * Froesch BA, Takayama S and Reed JC . (1998).

_J. Biol. Chem._, 273, 11660–11666. * Greenlee RT, Murray T, Bolden S and Wingo PA . (2000). _CA Cancer J. Clin._, 50, 7–33. * Gustavsson H, Welen K and Damber JE . (2005). _Prostate_, 62,

364–373. * Hashimoto I, Kodama J, Seki N, Hongo A, Yoshinouchi M, Okuda H and Kudo T . (2001). _Br. J. Cancer_, 85, 93–97. * Hatva E, Kaipainen A, Mentula P, Jaaskelainen J, Paetau A, Haltia

M and Alitalo K . (1995). _Am. J. Pathol._, 146, 368–378. * Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD and Wiegand SJ . (1999). _Science_, 284,

1994–1998. * Isaacs JT . (1999). _Urol. Clin. North Am._, 26, 263–273. * Jain RK, Safabakhsh N, Sckell A, Chen Y, Jiang P, Benjamin L, Yuan F and Keshet E . (1998). _Proc. Natl. Acad. Sci.

USA_, 95, 10820–10825. * Jia YT, Li ZX, He YT, Liang W, Yang HC and Ma HJ . (2004). _World J. Gastroenterol._, 10, 3261–3263. * Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk

E, Saksela O, Kalkkinen N and Alitalo K . (1996). _EMBO J._, 15, 1751. * Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N and Alitalo K . (1997). _EMBO

J._, 16, 3898–3911. * Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M and Alitalo K . (1995). _Proc. Natl. Acad. Sci. USA_, 92, 3566–3570. * Kang HY, Cho

CL, Huang KL, Wang JC, Hu YC, Lin HK, Chang C and Huang KE . (2004). _J. Bone Miner. Res._, 19, 1181–1190. * Keller SR, Lamphere L, Lavan BE, Kuhne MR and Lienhard GE . (1993). _Mol.

Reprod. Dev._, 35, 346–351; discussion 351–352. * Kimura Y, Watanabe M, Ohga T, Saeki H, Kakeji Y, Baba H and Maehara Y . (2003). _Oncol. Rep._, 10, 1747–1751. * Kops GJ and Burgering BM .

(1999). _J. Mol. Med._, 77, 656–665. * Kubo H, Fujiwara T, Jussila L, Hashi H, Ogawa M, Shimizu K, Awane M, Sakai Y, Takabayashi A, Alitalo K, Yamaoka Y and Nishikawa SI . (2000). _Blood_,

96, 546–553. * Kyprianou N, English HF and Isaacs JT . (1990). _Cancer Res._, 50, 3748–3753. * Lee J, Gray A, Yuan J, Luoh SM, Avraham H and Wood WI . (1996). _Proc. Natl. Acad. Sci. USA_,

93, 1988–1992. * Lin K, Dorman JB, Rodan A and Kenyon C . (1997). _Science_, 278, 1319–1322. * Marchio S, Primo L, Pagano M, Palestro G, Albini A, Veikkola T, Cascone I, Alitalo K and

Bussolino F . (1999). _J. Biol. Chem._, 274, 27617–27622. * Morris JZ, Tissenbaum HA and Ruvkun G . (1996). _Nature_, 382, 536–539. * Neuchrist C, Erovic BM, Handisurya A, Fischer MB,

Steiner GE, Hollemann D, Gedlicka C Saaristo A and Burian M . (2003). _Head Neck_, 25, 464–474. * Nicholson B and Theodorescu D . (2004). _J. Cell. Biochem._, 91, 125–150. * Ogg S, Paradis

S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA and Ruvkun G . (1997). _Nature_, 389, 994–999. * Oh WK and Kantoff PW . (1998). _J. Urol._, 160, 1220–1229. * Olofsson B, Jeltsch M,

Eriksson U and Alitalo K . (1999). _Curr. Opin. Biotechnol._, 10, 528–535. * Pepper MS . (2001). _Clin. Cancer Res._, 7, 462–468. * Pettaway CA, Pathak S, Greene G, Ramirez E, Wilson MR,

Killion JJ and Fidler IJ . (1996). _Clin. Cancer Res._, 2, 1627–1636. * Plymate SR, Tennant MK, Culp SH, Woodke L, Marcelli M, Colman I, Nelson PS, Carroll JM, Roberts Jr CT and Ware JL .

(2004). _Prostate_, 61, 276–290. * Ruohola JK, Valve EM, Karkkainen MJ, Joukov V, Alitalo K and Harkonen PL . (1999). _Mol. Cell Endocrinol._, 149, 29–40. * Sadar MD, Hussain M and

Bruchovsky N . (1999). _Endocr. Relat. Cancer_, 6, 487–502. * Schlessinger J . (2000). _Cell_, 103, 211–225. * Shatkina L, Mink S, Rogatsch H, Klocker H, Langer G, Nestl A and Cato AC .

(2003). _Mol. Cell. Biol._, 23, 7189–7197. * Sipos B, Klapper W, Kruse ML, Kalthoff H, Kerjaschki D and Kloppel G . (2004). _Am. J. Pathol._, 165, 1187–1197. * Skobe M, Hawighorst T, Jackson

DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K and Detmar M . (2001). _Nat. Med._, 7, 192–198. * Soker S, Takashima S, Miao HQ, Neufeld G and Klagsbrun M . (1998).

_Cell_, 92, 735–745. * Steiner H, Berger AP, Godoy-Tundidor S, Bjartell A, Lilja H, Bartsch G, Hobisch A and Culig Z . (2004). _Eur. J. Cancer_, 40, 1066–1072. * Stewart RJ, Panigrahy D,

Flynn E and Folkman J . (2001). _J. Urol._, 165, 688–693. * Tang Y, Zhang D, Fallavollita L and Brodt P . (2003). _Cancer Res._, 63, 1166–1171. * Tsurusaki T, Kanda S, Sakai H, Kanetake H,

Saito Y, Alitalo K and Koji T . (1999). _Br. J. Cancer_, 80, 309–313. * Veikkola T, Karkkainen M, Claesson-Welsh L and Alitalo K . (2000). _Cancer Res._, 60, 203–212. * Wang ZL, Chen Y, Zhou

B, Liang CY, Zhang L and Li RX . (2004). _Sichuan Da Xue Xue Bao Yi Xue Ban_, 35, 47–49. * Yonemura Y, Endo Y, Fujita H, Fushida S, Ninomiya I, Bandou E, Taniguchi K, Miwa K, Ohoyama S,

Sugiyama K and Sasaki T . (1999). _Clin. Cancer Res._, 5, 1823–1829. * Zeng Y, Opeskin K, Baldwin ME, Horvath LG, Achen MG, Stacker SA, Sutherland RL and Williams ED . (2004). _Clin. Cancer

Res._, 10, 5137–5144. Download references ACKNOWLEDGEMENTS We thank Dr Donald Tindall and Dr Debabrata Mukhopadhyay for their helpful discussion and Julie Lau for helping us to write the

manuscript. This work was partly supported by Career Development project in prostate spore grant (Mayo Clinic) (1 PSOCA91956-3) and New Investigator award grant from US Army Medical Research

and material Command (2B1636) of KD. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic Foundation,

Rochester, MN, USA Jinping Li, Enfeng Wang, Francesca Rinaldo & Kaustubh Datta Authors * Jinping Li View author publications You can also search for this author inPubMed Google Scholar *

Enfeng Wang View author publications You can also search for this author inPubMed Google Scholar * Francesca Rinaldo View author publications You can also search for this author inPubMed 

Google Scholar * Kaustubh Datta View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Kaustubh Datta. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Li, J., Wang, E., Rinaldo, F. _et al._ Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO

pathway. _Oncogene_ 24, 5510–5520 (2005). https://doi.org/10.1038/sj.onc.1208693 Download citation * Received: 27 December 2004 * Revised: 23 February 2005 * Accepted: 01 March 2005 *

Published: 09 May 2005 * Issue Date: 18 August 2005 * DOI: https://doi.org/10.1038/sj.onc.1208693 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative

KEYWORDS * VEGF-C * prostate cancer * metastasis * androgen * IGF-IR