Phosphorylation status of c-kit and epo receptors, and the presence of wild-type p53 confer in vitro resistance of murine erythroleukemic cells to celecoxib

ABSTRACT It is well established that selective COX-2 inhibitors exhibit potent effects against progression of select solid tumours. However, their effects on liquid tumours have not been

fully established. By taking advantage of murine Friend Disease we have shown a strong antileukemic effect of celecoxib by determining novel _in vitro_ targets. Western blot analyses

revealed the expression of COX-2 in a panel of Friend Virus-transformed, splenic-derived primary erythroleukemic blasts and established cell lines generated in our laboratory. We have shown

that celecoxib at concentrations as low as 20 _μ_ M significantly suppresses proliferation of the selected murine erythroleukemia cell line HB60-5. The greatest proliferative inhibition was

seen at 40 _μ_ M of celecoxib, resulting in apoptosis. Our results also demonstrate that treatment of the established murine erythroleukemia cell line HB60-5 with celecoxib results in

suppression of c-Kit and erythropoietin receptor (Epo-R) phosphorylation resulting in apoptosis, likely through decreased levels of survival factors. However, upon overexpression of c-Kit

alone in these cells a significant increase in survival and twofold increase in proliferation in the presence of celecoxib were observed (_P_<0.05). Finally, since responsiveness of our

murine erythroleukemia cell lines to celecoxib is above the reported physiologically achievable levels _in vivo_, we have provided _in vitro_ evidence to suggest that reduced sensitivity of

erythroleukemic cells to lower doses of celecoxib may be a consequence of the loss of wild-type _p53_. These findings are pivotal in addressing potential discrepancies associated with

sensitivity of murine erythroleukemic cells to celecoxib _in vitro_ versus _in vivo_. Access through your institution Buy or subscribe This is a preview of subscription content, access via

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T-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA Article Open access 23 January 2025 REFERENCES * Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P and Ogier-Denis E . (2002). _J.

Biol. Chem._, 277 (31), 27613–27621. * Bao H, Jacobs-Helber SM, Lawson AE, Penta K, Wickrema A and Sawyer ST . (1999). _Blood_, 39, 3757–3773. * Beazer-Barclay Y, Levy DB, Moser AR, Dove WF,

Hamilton SR, Vogelstein B and Kinzler KW . (1996). _Carcinogenesis_, 17, 1757–1760. * Ben-David Y, Lavigueur A, Cheong GY and Bernstein A . (1990). _The New Biologist_, 2, 1015–1023. *

Berman KS, Verma UN, Harburg G, Minna JD, Cobb MH and Gaynor RB . (2002). _Clin. Cancer Res._, 8, 354–360. * Bittorf T, Buchse T, Sasse T, Jaster R and Brock J . (2001). _Cell Signal_, 9,

673–681. * Chan G, Boyle JO, Yang EK, Zhang F, Sacks PG, Shah JP, Edelstein D, Soslow RA, Koki AT, Woerner BM, Masferrer JL and Dannenberg AJ . (1999). _Cancer Res._, 59, 991–994. * DuBois

RN, Giardello FM and Smalley WE . (1996). _Gastroenterol. Clin. North Am._, 25, 773–791. * Fischer SM, Lo HH, Gordon GB, Seibert K, Kelloff G, Lubet RA and Conti CJ . (1999). _Mol.

Carcinog._, 25, 231–240. * Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR and Offerhaus GJ . (1993). _N. Eng. J. Med._, 328, 1313–1316. *

Harris RE, Alshafie GA, Abou-Issa H and Seibert K . (2000). _Cancer Res._, 60, 2101–2103. * Howard J, Ung Y, Adachi D and Ben-David Y . (1996). _Cell Growth Differ._, 7, 1651–1660. * Howard

JC, Li Q, Chu W, Zochodne B, Kapoor M, Ung Y, Rosen K and Ben-David Y . (2001). _Oncogene_, 20, 2291–2300. * Hwang D, Scollard D, Byrne J and Levine E . (1998). _J. Natl. Cancer Inst._, 90,

455–460. * Johnson P, Chung S and Benchimol S . (1993). _Mol. Cell. Biol._, 13, 1456–1463. * Li YJ, Higgins RR, Pak BJ, Shivdasani RA, Ney PA, Archer M and Ben-David Y . (2001). _Mol. Cell.

Biol._, 21, 73–80. * Lim JT, Piazza GA, Han EK, Delohery TM, Li H, Finn TS, Buttyan R, Yamamoto H, Sperl GJ, Brendel K, Gross PH, Pamukcu R and Weinstein IB . (1999). _Biochem. Pharmacol._,

58, 1097–1107. * Lin MT, Lee RC, Yang PC, Ho FM and Kuo ML . (2001). _J. Biol. Chem._, 276, 48997–49002. * Mekori YA, Gilfillan AM, Akin C, Hartmann K and Metcalfe DD . (2001). _J. Clin.

Immunol._, 21, 171–174. * Munroe DG, Peacock JW and Benchimol S . (1990). _Mol. Cell. Biol._, 10, 3307–3313. * Nakanishi Y, Kamijo R, Takizawa K, Hatori M and Nagumo M . (2001). _Eur. J.

Cancer_, 37, 1570–1578. * Sachinidis A, Gouni-Berthold I, Seul C, Seewald S, Ko Y, Schmitz U and Vetter H . (1999). _Br. J. Pharmacol._, 128, 1761–1771. * Shamma A, Yamamoto H, Doki Y, Okami

J, Kondo M, Fujiwara Y, Yano M, Inoue M, Matsuura N, Shiozaki H and Monden M . (2000). _Clin. Cancer Res._, 61, 229–1238. * Shibuya T and Mak T . (1983). _Proc. Natl. Acad. Sci., USA_, 80,

3721–3725. * Subbaramaiah K, Altorki N, Chung WJ, Mestre JR, Sampat A and Dannenberg AJ . (1999). _J. Biol. Chem._, 274, 10911–10915. * Tamir A, Howard J, Higgins RR, Li YJ, Berger L,

Zacksenhaus E, Reis M and Ben-David Y . (1999). _Mol Cell Biol._, 19, 4452–4464. * Torrance CJ, Jackson PE, Montgomery E, Kinzler KW, Vogelstein B, Wissner A, Nunes M, Frost P and Discafani

CM . (2000). _Nat. Med._, 6, 1024–1028. * Tsujii M and DuBois RN . (1995). _Cell_, 83, 493–501. * Tsujii M, Kuwano S and DuBois RN . (1997). _Natl. Acad. Sci., USA_, 94, 3336–3340. *

Williams CS, Watson AJM, Sheng H, Helou R, Shao J and DuBois RN . (2000). _Cancer Res._, 60, 6045–6051. * Wong KS, Li YJ, Howard J and Ben-David Y . (1999). _Oncogene_, 18, 5525–5534. *

Zhang L, Yu J, Park BH, Kinzler KW and Vogelstein B . (2000). _Science_, 90, 989–992. Download references ACKNOWLEDGEMENTS We are grateful for Dr R. Rottapel for his kind gift of the

GP+E-86/c-Kit+, /LXS packaging cell lines. We also thank Drs J. Filmus, S. Benchimol and B. Pak for their comments concerning the work presented in this study, and also Ms. Lynda Woodcock

for assistance in the preparation of the manuscript. This work was supported by a grant from the National Cancer Institute of Canada (NCIC) and a contract fund from Pharmacia/Monsanto. Dave

Cervi and Amandine HL Truong are supported by studentships from the Canadian Institute for Health Research. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medical Biophysics,

Sunnybrook and Women's College Health Sciences Centre and Toronto Sunnybrook Regional Cancer Centre, University of Toronto, M4N 3M5, Ontario, Canada David Cervi, Amandine H L Truong, 

Jane S Lee, Natasha Sukhai, You-Jun Li & Yaacov Ben-David * IPSOGEN, 2 Bd Luce 13008, Marseille, France Alane Koki * Department of Molecular and Cellular Biology, Sunnybrook and

Women's College Health Sciences Centre and Toronto Sunnybrook Regional Cancer Centre, University of Toronto, M4N 3M5, Ontario, Canada Yaacov Ben-David Authors * David Cervi View author

publications You can also search for this author inPubMed Google Scholar * Amandine H L Truong View author publications You can also search for this author inPubMed Google Scholar * Jane S

Lee View author publications You can also search for this author inPubMed Google Scholar * Natasha Sukhai View author publications You can also search for this author inPubMed Google Scholar

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PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Cervi, D., Truong, A., Lee, J. _et al._ Phosphorylation status of c-Kit and Epo receptors, and the presence of

wild-type p53 confer _in vitro_ resistance of murine erythroleukemic cells to Celecoxib. _Oncogene_ 23, 2305–2314 (2004). https://doi.org/10.1038/sj.onc.1207400 Download citation * Received:

12 September 2003 * Revised: 07 November 2003 * Accepted: 20 November 2003 * Published: 26 January 2004 * Issue Date: 25 March 2004 * DOI: https://doi.org/10.1038/sj.onc.1207400 SHARE THIS

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * erythroleukemia * celecoxib * c-Kit phosphorylation * p53 status * resistance