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Published 12 September 2005. doi:10.1083/jcb.200501040
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 6, 903-912
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Article

 FOXO1a acts as a selective tumor suppressor in alveolar rhabdomyosarcoma

Philippe R.J. Bois1,2, Kamel Izeradjene3, Peter J. Houghton4, John L. Cleveland1, Janet A. Houghton3, and Gerard C. Grosveld2

1 Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105
2 Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105
3 Department of Hematology–Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105
4 Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105

Correspondence to Gerard C. Grosveld: gerard.grosveld{at}stjude.org

Rhabdomyosarcoma (RMS), the most common pediatric soft-tissue sarcoma, has two major histological subtypes: embryonal RMS (ERMS), which has a favorable prognosis, and alveolar RMS (ARMS), which has a poor outcome. Although both forms of RMS express muscle cell–specific markers, only ARMS cells express PAX3-FOXO1a or PAX7-FOXO1a chimeric proteins. In mice, Pax3 and Pax7 play key roles in muscle cell development and differentiation, and FoxO1a regulates myoblast differentiation and fusion; thus, the aberrant regulation of these proteins may contribute to the development of ARMS. In this paper, we report that FOXO1a is not expressed in primary ARMS tumors or ARMS-derived tumor cell lines and that restoration of FOXO1a expression in ARMS cells is sufficient to induce cell cycle arrest and apoptosis. Strikingly, the effects of FOXO1a are selective, as enforced expression of FOXO1a in ERMS-derived tumor cell lines had no effect. Furthermore, FOXO1a induced apoptosis in ARMS by directly activating the transcription of caspase-3. We conclude that FOXO1a is a potent and specific tumor suppressor in ARMS, suggesting that agents that restore or augment FOXO1a activity may be effective as ARMS therapeutics.

Abbreviations used in this paper: ARMS, alveolar RMS; Casp, caspase-3; ChIP, chromatin immunoprecipitation; ER, estrogen receptor; ERMS, embryonal RMS; FOXO1a-TM, dominant-active FOXO1a; FOXO1a-TM-ERTAM, tamoxifen-regulated form of FOXO1a-TM; FOXO1a-WT, wild-type FOXO1a; MyoHC, myosin heavy chain; RMS, rhabdomyosarcoma; SEAP, secreted alkaline phosphatase.


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