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Hammerhead Ribozyme-Mediated Cleavage of the Human Insulin-Like Growth Factor-II Ribonucleic Acid in Vitro and in Prostate Cancer Cells¹

Department of Molecular Biology (Z-D.X., L.O., N.-S.L., J.J.R., Y.F.-Y.) Beckman Research Institute of the City of Hope and Department of Urology (L.O., M.H.K.), City of Hope Medical Center, Duarte, California 91010; and Department of Biochemistry, Physiology, and Medicine (S.M.), Loma Linda University, Jerry L. Pettis Veterans Affairs Medical Center, Loma Linda, California 92357

Address all correspondence and requests for reprints to: Yoko Fujita-Yamaguchi, Ph.D., Department of Molecular Biology, Beckman Research Institute of the City of Hope, 1450 East Duarte Road, Duarte, California 91010. E-mail: yyamaguchi{at}coh.org

Insulin-like growth factor (IGF)-II plays an important role in fetal growth and development. IGFs are potent mitogens for a variety of cancer cells. A paracrine/autocrine role of IGF-II in the growth of breast and prostate cancer cells has been suggested. To test the role of IGF-II in cancer cell growth, hammerhead ribozymes targeted to human IGF-II RNA were constructed. Single (R)- and double (RR)-ribozymes were catalytically active in vitro whereas mutant ribozymes (M or MM) did not cleave IGF-II RNA. RR was more active than R. In human prostate cancer PC-3 cells, both R and RR similarly suppressed IGF-II messenger RNA (mRNA) levels (40%) compared with the level in parental or M-expressing PC-3 cells. Polymerase II and III promoter-driven R similarly suppressed IGF-II mRNA levels. Suppression of IGF-II mRNA levels by R was associated with suppression of IGF-II protein levels. R- (or RR-) expressing PC-3 cells did not grow under serum-starved conditions and showed prolonged doubling times in the presence of 10% FCS compared with those of parental or M-expressing cells. These results substantiated that IGF-II plays a critical role in prostate cancer cell growth.

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