Endogenous fibroblast growth factor-1 or fibroblast growth factor-2 modulate prostate cancer cell proliferation.

We constructed expression vectors containing either rat fibroblast growth factor (FGF)-1 for FGF-2 cDNA cloned in either the sense orientation or antisense orientation relative to the metallothionein promoter of plasmid pMTneo.1. Stable AXC/SSh rat prostate cancer cell transfectants expressing either chimeric FGF-1-sense, chimeric FGF-1-antisense, or chimeric FGF-2-antisense transcripts were obtained. Stable transfectants expressing chimeric FGF-2-sense transcripts were not obtained. Control, sense, and antisense transfectants expressed endogenous FGF-1 and endogenous FGF-2 transcripts, implying that transfection did not eliminate endogenous FGF transcripts. Control transfectants and sense transfectants contained FGF-1 isoforms having a mass of 16.4 or 17.3 kDa and FGF-2 isoforms having a mass of 17, 19.5, or 21.5 kDa. Significantly, adult AXC/SSh rat prostate contained only the 17.3 kDa FGF-1 isoform and the 17 kDa FGF-2 isoform, indicating that neoplastic transformation was associated with elaboration of novel, prostate epithelial cell-derived FGF-2 isoforms. FGF-1 antisense RNA expression eliminated transfectant FGF-1 isoforms without affecting FGF-2 isoform content. Similarly, FGF-2-antisense RNA expression eliminated the transfectant 21.5 kDa FGF-2 isoform, diminished the 19.5 kDa FGF-2 isoform content, and reduced the 17 kDa FGF-2 isoform content to barely detectable levels without affecting the FGF-1 isoform content. This established that FGF-antisense RNAs specifically inhibited translation of cognate, endogenous FGF transcripts. Doubling times of control transfectants and sense transfectants were indistinguishable and were not affected by including FGF-1 or FGF-2 in the culture medium. Doubling times of FGF-1-antisense or FGF-2-antisense transfectants were 1.3- to 1.4-fold greater than those of control transfectants or sense transfectants, and either exogenous FGF-1 or exogenous FGF-2 decreased antisense transfectant doubling times to values indistinguishable from those of control transfectants or sense transfectants. This established that with regard to prostate cancer cell proliferation: (a) endogenous FGF-1 cannot substitute for endogenous FGF-2 eliminated by FGF-2-antisense RNA expression; and (b) endogenous FGF-2 cannot substitute for endogenous FGF-1 eliminated by FGF-1-antisense RNA expression. In contrast, either exogenous FGF-1 or exogenous FGF-2 decreased antisense transfectant doubling time. The results of these studies establish that endogenous FGF-1 and endogenous FGF-2 modulate prostate cancer cell proliferation and imply that FGF-1 and FGF-2 of endogenous and exogenous origin conjointly control aspects of prostate cancer cell homeostasis. Our findings suggest complex interaction between components of prostate cancer cell regulatory processes and endogenously produced and exogenously accessible FGF-1 and FGF-2.