Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells

Raya Saab, Jennifer L. Bills, Alexander P. Miceli, Colleen M. Anderson, Joseph D. Khoury, David D. Fry, Fariba Navid, Peter J. Houghton, Stephen X. Skapek

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Myoblast cell cycle exit and differentiation are mediated in part by down-regulation of cyclin D1 and associated cyclin-dependent kinase (Cdk) activity. Because rhabdomyosarcoma may represent a malignant tumor composed of myoblast-like cells failing to exit the cell cycle and differentiate, we considered whether excess Cdk activity might contribute to this biology. Cyclin D-dependent Cdk4 and Cdk6 were expressed in most of a panel of six human rhabdomyosarcoma-derived cell lines. Cdk4 was expressed in 73% of alveolar and embryonal rhabdomyosarcoma tumors evaluated using a human tissue microarray. When challenged to differentiate by mitogen deprivation in vitro, mouse C2C 12 myoblasts arrested in G1 phase of the cell cycle, whereas four in the panel of rhabdomyosarcoma cell lines failed to do so. C2C12 myoblasts maintained in mitogen-rich media and exposed to a Cdk4/Cdk6 inhibitor PD 0332991 accumulated in G1 cell cycle phase. Similar treatment of rhabdomyosarcoma cell lines caused G1 arrest and prevented cell accumulation in vitro, and it delayed growth of rhabdomyosarcoma xenografts in vivo. Consistent with a role for Cdk4/Cdk6 activity as a regulator of myogenic differentiation, we observed that PD 0332991 exposure promoted morphologic changes and enhanced the expression of muscle-specific proteins in cultured myoblasts and in the Rh30 cell line. Our findings support the concept that pharmacologic inhibition of Cdk4/Cdk6 may represent a useful therapeutic strategy to control cell proliferation and possibly promote myogenic differentiation in rhabdomyosarcoma.

Original languageEnglish (US)
Pages (from-to)1299-1308
Number of pages10
JournalMolecular Cancer Therapeutics
Volume5
Issue number5
DOIs
StatePublished - May 2006

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Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinase 4
Rhabdomyosarcoma
Myoblasts
Cell Cycle
Cell Line
Cyclin-Dependent Kinases
Mitogens
Alveolar Rhabdomyosarcoma
Embryonal Rhabdomyosarcoma
Cyclin D
Muscle Proteins
Cyclin D1
G1 Phase
Heterografts
Cell Differentiation
Neoplasms
Down-Regulation
Cell Proliferation
Growth

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells. / Saab, Raya; Bills, Jennifer L.; Miceli, Alexander P.; Anderson, Colleen M.; Khoury, Joseph D.; Fry, David D.; Navid, Fariba; Houghton, Peter J.; Skapek, Stephen X.

In: Molecular Cancer Therapeutics, Vol. 5, No. 5, 05.2006, p. 1299-1308.

Research output: Contribution to journalArticle

Saab, Raya ; Bills, Jennifer L. ; Miceli, Alexander P. ; Anderson, Colleen M. ; Khoury, Joseph D. ; Fry, David D. ; Navid, Fariba ; Houghton, Peter J. ; Skapek, Stephen X. / Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 5. pp. 1299-1308.
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