Apoptosis in v-myc transformation of myelomonocytic cells and its modulation by CSF-1.
c-myc is a proto-oncogene essential for cell growth. When activated, its expression can lead to uncontrolled cell proliferation, transformation and tumorigenesis. The cell line tEMmyc4 is a murine myelomonocytic cell line that was established following transformation by v-myc. It has a high level of v-myc expression and constitutively expresses endogenous CSF-1, the monocytic growth and viability factor. Under growth restricting conditions (high cell density serum deprivation, heat shock, or dexamethasone addition) cells of this line were found to undergo cell death through apoptosis. The induction of apoptosis by dexamethasone was associated with a decrease in constitutive CSF-1 expression without significant change in v-myc expression. Exogenous CSF-1 rescued these cells from dexamethasone induced-apoptosis. In vivo studies showed that tEMmyc4 cells were tumorigenic in syngeneic animals despite exhibiting some spontaneous apoptosis within the tumour mass. Co-administration of dexamethasone with the tumour cells significantly inhibited tumor development and the administration of dexamethasone to mice with established tumors resulted in tumor regression in all mice. This regression was associated with a high level of apoptosis and necrosis in the tumors. This study shows a correlation between the in vitro and in vivo induction of apoptosis and indicates that cancer cells bearing activated oncogenes may be more sensitive to apoptosis induction by chemotherapeutic agents.
Dolnikov
A
A
Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital,Darlinghurst, NSW, Australia.
Ward
R L
RL
Hawkins
N J
NJ
Symonds
G
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D016259:Genes, myc; D006133:Growth Substances / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology*
D006133:Growth Substances; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor