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Abstract
BackgroundPolyamines and ornithine decarboxylase (ODC) are essential for cell proliferation. DL-α-difluoromethylornithine (DFMO), a synthetic inhibitor of ODC, induces G1 arrest through dephosphorylation of retinoblastoma protein (pRb). The effect of DFMO on cell growth of pRb deficient cells is not known. We examined the effects of DFMO on pRb deficient human retinoblastoma Y79 cell proliferation and its molecular mechanism.MethodsUsing cultured Y79 cells, the effects of DFMO were studied by using polyamine analysis, western blot, gel shift, FACS and promoter analysis.ResultsDFMO suppressed the proliferation of Y79 cells, which accumulated in the G1 and S phase. DFMO induced p27/Kip1 protein expression, p107 dephosphorylation and accumulation of p107/E2F-4 complex in Y79 cells.ConclusionThese results indicate that p107 dephosphorylation and accumulation of p107/E2F-4 complex is involved in G1 and S phase arrest of DFMO treated Y79 cells.
Highlights
Polyamines and ornithine decarboxylase (ODC) are essential for cell proliferation
Since little is known about effects of DFMO on cell growth of pRb deficient cells, we examined whether DFMO has an anti-proliferative effect and how DFMO affects cell cycle in human retinoblastoma Y79 cells that lack functional pRb protein
Inhibition of Y79 cell growth and induction of G1 and S phase arrest by DFMO Preliminary experiment showed that DFMO (1–5 mM) inhibited Y79 cell growth in a dose-dependent manner
Summary
Polyamines and ornithine decarboxylase (ODC) are essential for cell proliferation. DL-α-difluoromethylornithine (DFMO), a synthetic inhibitor of ODC, induces G1 arrest through dephosphorylation of retinoblastoma protein (pRb). We examined the effects of DFMO on pRb deficient human retinoblastoma Y79 cell proliferation and its molecular mechanism. Depletion of polyamines by DL-α-difluoromethylornithine (DFMO), a specific inhibitor of ODC, has been reported to inhibit growth of various kinds of cells [3,4,9,10,11]. DFMO induces expression of CDK inhibitors such as p21 and p27 [12,13,14] and G1 arrest associated with hypophosphorylation of pRb [13]. It is established that increased expression of p16, p21 or p27 suppreses CDK activities, which leads to cell cycle arrest [15,16]
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