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The 20-Kilodalton (kDa) Human Growth Hormone (hGH) Differs from the 22-kDa hGH in the Effect on the Human Prolactin Receptor

Pharmaceuticals Section, Life Sciences Laboratory, Performance Materials R&D Center, Mitsui Chemicals, Inc., 1144 Togo, Mobara-shi, Chiba 297-0017, Japan

Address all correspondence and requests for reprints to: Masaru Honjo, Ph.D., Pharmaceuticals Section, Life Sciences Laboratory, Performance Materials R&D Center, Mitsui Chemicals, Inc., 1144, Togo, Mobara-shi, Chiba 297-0017, Japan. E-mail: masaru.honjo{at}mitsui-chem.co.jp

Previously we have demonstrated that 20-kDa human GH (20K-hGH) is a full agonist for hGH receptor (hGHR) even though its complex formation with hGHR and hGH-binding protein differs from that of 22-kDa human GH (22K-hGH). In this study, we focused on the effect of 20K-hGH on human PRL receptor (hPRLR). To elucidate the effects of 20K-hGH on hPRLR and compare them with those of 22K-hGH, we prepared two cells stably expressing full-length hPRLR, Ba/F3-hPRLR and CHO-hPRLR. In the proliferation of Ba/F3-hPRLR cells, which can grow in a dose-response to lactogenic hormones, both 20K- and 22K-hGH exhibited bell-shaped curves in the absence of exogenous zinc ion (Zn²⁺); however, the curve of 20K-hGH was shifted to a 10-fold higher concentration than that of 22K-hGH in view of EC₅₀ value (the EC₅₀ of 20K- and 22K-hGH were 15 nM and 1.5 nM, respectively). Addition of Zn²⁺ up to 25 µM increased the activities of both 20K- and 22K-hGH; however, the enhancement by Zn²⁺ was greater in 20K-hGH than in 22K-hGH, thereby the activities of both hGH isoforms reached the same level at 25 µM Zn²⁺. Nevertheless, in the presence of 0.25–1 µM free Zn²⁺, which is equal in human serum, the activity of 20K-hGH was still lower than that of 22K-hGH. The modest effect of 20K-hGH on activating hPRLR in the absence of Zn²⁺ was confirmed in the rat serine protease inhibitor 2.1 (Spi2.1) gene promoter activation and JAK2/Stat5 tyrosine phosphorylation in CHO-hPRLR. In addition, in human breast cancer cell T-47D, 20K-hGH was proved to stimulate Stat5 tyrosine phosphorylation to much lower degree than 22K-hGH via not hGHR but hPRLR. Taken together, our data suggest that 20K-hGH may be a weaker agonist for hPRLR than 22K-hGH in the human body; therefore 20K-hGH may alleviate the hPRLR-mediated side-effects such as breast cancer when administered to human body.

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