Okadaic Acid: A Reversible Inhibitor of Neoplastic Transformation of Mouse Fibroblasts

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Abstract
Okadaic acid (OA) is a potent inhibitor of serine/threonine-specific protein phosphatases types 1 and 2A at nanomolar concentrations in cell-free assays and has tumor promoting activity in vivo. We have found that at non-toxic, nanomolar concentrations, OA concentration dependently inhibits the induction of focus-forming transformed cells by the “complete" and “two-stage" protocols in the C3H/10T1/2 mouse fibroblast transformation assay. This inhibitory effect was fully reversible upon removal of OA from the culture medium of carcinogen-treated cells, indicating that OA was not selectively toxic to initiated or transformed cells. Additional treatment with the phorbol ester tumor promoter, TPA, was required to promote the induction of transformed cells after the removal of OA in the two-stage transformation assay. At concentrations that inhibited neoplastic transformation, OA inhibited a type 2A-like phosphohistone protein phosphatase in homogenates of C3H/10T1/2 cells. It is postulated that OA inhibited an early protein phosphatase-sensitive event in the process of in vitro neoplastic transformation by C3H/10T1/2 fibroblasts and had the effect of maintaining carcinogen-treated cells in an initiated state.