INDUCTION OF MINISATELLITE MUTATION IN NIH 3T3 CELLS BY TREATMENT WITH THE TUMOR PROMOTER OKADAIC ACID

Okadaic acid (OA) is a strong tumor promoter of mouse skin carcinogene sis and also a potent inhibitor of serine/threonine protein phosphatas es. OA induces various genetic alterations in cultured cells, such as diphtheria-toxin-resistance mutations, sister chromatid exchange, excl usion of exogenous transforming oncogenes, and gene amplification, The present study revealed that it caused minisatellite mutation (MSM) at a high frequency in NIH 3T3 cells, although no microsatellite mutatio n was found, Nine of 31 clones (29%) exhibited MSM after 6 days of OA treatment, as opposed to only 1 of 30 clones (3%) without OA exposure, Moreover, NIH 3T3 cells treated with OA acquired tumorigenicity in nu de mice, giving rise to 7 tumors within 25 weeks in 20 sites where 3 x 10(6) cells were injected, In contrast, the same numbers of untreated cells gave rise to only one tumor, and the tumor grew much slower. Al l of three OA-induced tumors examined manifested the MSM. The findings thus point to a molecular mechanism by which OA could function as a t umor promoter, and also the biological relevance of the induction of M SM in the tumorigenic process by OA.