The effect of rapamycin on DNA synthesis in multiple tissues from late gestation fetal and postnatal rats

Area of Science:

• Cell Biology
• Developmental Biology
• Pharmacology

Background:

• Rapamycin inhibits the mammalian target of rapamycin (mTOR) pathway, affecting cell proliferation.
• While normal cells in culture are sensitive, many malignant cells exhibit rapamycin resistance.
• Previous studies showed fetal liver DNA synthesis is rapamycin-resistant despite mTOR pathway attenuation.

Purpose of the Study:

• To investigate rapamycin's effects on DNA synthesis and mTOR/S6K signaling in various rat tissues during late gestation and early postnatal development.
• To compare rapamycin sensitivity in normal tissue growth versus liver regeneration.

Main Methods:

• Administration of rapamycin to fetal and early postnatal rats.
• Analysis of DNA synthesis rates in major organs (heart, intestine, kidney, liver).
• Assessment of mTOR/S6K pathway activity via ribosomal protein S6 phosphorylation.
• Evaluation of rapamycin's effect on hepatocyte proliferation during liver regeneration.

Main Results:

• Rapamycin did not affect DNA synthesis in fetal and early postnatal heart, intestine, and kidney, despite reduced S6 phosphorylation.
• Basal cellular proliferation in these major organs was rapamycin-resistant.
• Mature hepatocytes undergoing liver regeneration were highly sensitive to rapamycin's antiproliferative effects.

Conclusions:

• Basal cellular proliferation in diverse tissues of fetal and early postnatal rats is independent of mTOR/S6K signaling and resistant to rapamycin.
• The antiproliferative effects of rapamycin observed in cell culture are not replicated in normal tissue growth and remodeling.
• Differential sensitivity to rapamycin exists between basal proliferation and tissue regeneration processes.