The physiology and pathophysiology of rapamycin resistance: implications for cancer

Area of Science:

• Cell Biology
• Developmental Biology
• Pharmacology

Background:

• Rapamycin inhibits mTOR, a key regulator of cell growth and proliferation.
• Cancer cells often exhibit resistance to rapamycin's anti-proliferative effects.
• Developing organisms present a unique context for studying cellular responses to growth inhibitors.

Purpose of the Study:

• To investigate rapamycin resistance in normal cell proliferation during fetal and neonatal development.
• To identify mechanisms underlying resistance to rapamycin's anti-proliferative effects in developing tissues.
• To explore the relationship between mTOR signaling, cell cycle progression, and gene expression in the context of rapamycin resistance.

Main Methods:

• Administered rapamycin to fetal and neonatal rats.
• Assessed hepatocyte proliferation and cell cycle progression (cyclin E-dependent kinase activity).
• Analyzed ribosomal biogenesis, protein translation, and gene expression changes in response to rapamycin in vitro and in vivo.

Main Results:

• Fetal and neonatal rat tissues, particularly hepatocytes, showed resistance to rapamycin's anti-proliferative effects.
• Ribosomal biogenesis and cap-dependent translation were insensitive to rapamycin despite mTOR pathway sensitivity.
• Cell cycle progression, specifically cyclin E-dependent kinase activity, was a critical point of resistance.
• mTOR-regulated gene expression changes were independent of proliferation effects and involved metabolic genes.

Conclusions:

• Normal cellular proliferation in developing organisms can be independent of mTOR signaling.
• Cyclin E-containing complexes are crucial for rapamycin sensitivity.
• mTOR modulates metabolic gene expression in cells resistant to rapamycin's anti-proliferative actions.