Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
MODULATION OF CANCER PHENOTYPE BY OKADAIC ACID AND POLY (ADP-RIBOSE) POLYMERASE INHIBITOR-ASSOCIATED LOSS OF TRANSFECTED ONCOGENES
Serono Symp Publ Raven Press; 82:317-26 1991. Unique Identifier : AIDSLINE ICDB/92680117 Sugimura T; Fujiki H; Nagao M; Suganuma M; Shima H; Nakayasu M; Natl. Cancer Center Res. Inst., 1-1 Tsukiji 5-chome, Chuo-ku,; Tokyo 104, Japan
Abstract:
Okadaic acid (OA) is a skin irritant and tumor promoter isolated from croton oil and other sources. NIH3T3 cells that had been transformed morphologically by activated c-raf coding for serine/threonine-kinase or activated c-ret (ret II) coding for tyrosine kinase, were cultured in the presence of 8 ng/ml of okadaic acid for several days. This concentration slightly suppressed the growth of raf-transformed cells but did not affect the ret II-transformed cells, at exponential phase. However, in almost all the cells, the transformed morphology disappeared and became flattened and the cells lost their capacity to grow in soft agar. Gradual return from the flat reversion phenotype to the transformed phenotype was observed after removal of OA from the culture medium. NIH3T3 cells transformed by polyoma middle T also lost their malignant phenotype during 4 days in the presence of 8 ng/ml OA. In the course of studies of malignant phenotype of NIH3T3 cells transformed with activated Ha-ras, it was noticed that flat reversion occurred when cells were cultured in the presence of 5 mM benzamide, an inhibitor of poly(ADP-ribose) polymerase inhibitor. DNAs from cloned cells with transformed or flat phenotypes were subjected to Southern blot analysis. Transfected oncogenes had been lost from the flattened cells. This loss was subsequently observed for various transfected oncogenes, including human activated Ha-ras, human activated N-ras, rat activated Ki-ras, rat activated raf, and human ret II. Other poly(ADP-ribose) polymerase inhibitors, such as coumarin and luminol, had similar effects. Since poly(ADP-ribose) polymerase inhibitors delay the rejoining of strand scissions of DNA, this might create favorable conditions for deletion of transfected DNA sequences. The fact that the poly(ADP-ribose) inhibitor-induced reversion of malignant phenotype was accompanied by loss of transfected oncogenes may be of profound significance. If this occurs also for proviral DNA sequences integrated into host cell DNA, it would open up an entirely new approach to the control of neoplasms related to hepatitis B virus, human papilloma virus, human T-cell lymphotropic virus (HTLV)-I, HTLV-II, and HIV. (22 Refs)
Keywords: Animal Benzamides/PHARMACOLOGY Ethers, Cyclic/CHEMISTRY/*PHARMACOLOGY *Gene Expression Genes, ras/GENETICS Mice Neoplasms/GENETICS NAD+ ADP-Ribosyltransferase/ANTAGONISTS & INHIB Oncogene Proteins/GENETICS Phosphoprotein Phosphatase/GENETICS Signal Transduction Transfection 3T3 Cells/DRUG EFFECTS MONOGRAPH
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
