The cAMP analog 8-Cl-cAMP inhibits growth and induces differentiation and apoptosis in retinoblastoma cells.
Retinoblastomas appear to be derived from a multipotential stem cell of the retina, due to alterations of the Rb1 gene. These tumors arise only within a discrete time frame during childhood, prior to terminal differentiation of the retinal precursor cells. Treatment of retinoblastoma cells with certain agents can induce a partial differentiation of cell types resembling those of the mature retina, such as rod and cone photoreceptors, glia, conventional neurons and pigment epithelia. We have tested the effects of 8-Cl-cAMP, a synthetic analog of cAMP which preferentially binds to and activates the RII subunit of protein kinase A on the Y-79 retinoblastoma cell line in vitro. Y-79 cells treated with 8-Cl-cAMP produced short, branching processes and showed a substantial increase in staining for neuron-specific enolase, a marker for conventional neuronal differentiation. In contrast, dibutyryl-cAMP gives a strong increase in the glial marker glial acidic fibrillary protein. Y-79 cell proliferation was strongly inhibited by 8-Cl-cAMP at concentrations as low as 5-25 microM. 8-Cl-cAMP significantly increased the rate of apoptosis of Y-79 cells in a dose-dependent manner. It also modulated expression of the RI regulatory subunit of intracellular cAMP-dependent protein kinase A, which is produced in abnormal quantities by Y-79 cells. A decrease in protein production was observed, with no clear effect on the RI subunit mRNA expression, suggesting that RI regulation occurs post-transcriptionally.
Fassina
G
G
Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Aluigi
M G
MG
Gentleman
S
S
Wong
P
P
Cai
T
T
Albini
A
A
Noonan
D M
DM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002648:Child; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000737:chemistry; D053938:DNA Fragmentation; D005134:Eye Neoplasms; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D010751:Phosphopyruvate Hydratase / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D012175:Retinoblastoma; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D046911:Macromolecular Substances; D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003994:Bucladesine; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D010751:Phosphopyruvate Hydratase