Induction of apoptosis and inhibition of papilloma formation may signal a new role for okadaic acid.
Okadaic acid (OA), a tumor promoter in the mouse skin carcinogenesis model, has been shown to induce apoptosis in tumor cell lines that harbor H-ras mutations. We examined the effects of OA on mouse keratinocytes with (308) and without (C50) H-ras mutation in vitro and in an in vivo system. Following exposure to varying concentrations of OA over time, the effects of OA in vitro were assessed using microscopic, biochemical and flow cytometric techniques. OA effects on the cells included incorporation of propidium iodide, externalization of phosphatidylserine, and development of hypodiploidy. 308 cells demonstrated typical DNA ladder formation, rapid chromatin and nuclear condensation, while C50 cells demonstrated delayed chromatin condensation and nuclear fragmentation, but no DNA ladder formation. In vivo, OA elicited delayed papilloma formation and reduced tumor multiplicity. Though its mechanism of action is not fully known, we found that OA-induced inhibition of the clonal expansion of initiated cells may be related to the presence or absence of H-ras mutation.
Elegbede
J Abiodun
JA
Chemistry Department and UNLV Cancer Institute, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4003, USA. belegbede@ccmail.nevada.edu
Hayes
Kristie
K
Schell
Kathleen
K
Oberley
Terry D
TD
Verma
Ajit K
AK
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D053938:DNA Fragmentation / Q000187:drug effects; D004171:Diploidy; D004195:Disease Models, Animal; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008854:Microscopy, Electron; D019319:Okadaic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D010212:Papilloma / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D010718:Phosphatidylserines / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology
D010718:Phosphatidylserines; D019319:Okadaic Acid; D015127:9,10-Dimethyl-1,2-benzanthracene