Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus

Area of Science:

• Cellular Biology
• Molecular Biology
• Oncology

Background:

• The unfolded protein response (UPR) is a conserved cellular stress response in eukaryotes.
• mTOR inhibitors like rapamycin are used as anticancer agents.
• The precise mechanism of action for these drugs, particularly in relation to cellular stress responses, requires further elucidation.

Purpose of the Study:

• To investigate the effect of mTOR inhibitors rapamycin and temsirolimus on the UPR in sarcoma cells.
• To determine if the UPR induction by these drugs is linked to their known mTOR inhibitory function.
• To explore the potential of UPR activation as a biomarker for therapeutic response in cancer treatment.

Main Methods:

• Treatment of sarcoma cells with rapamycin and temsirolimus.
• Isolation and analysis of ribosomes from treated cells.
• Assessment of rRNA modification and UPR activation markers (e.g., eIF2 alpha phosphorylation, Xbp-1 splicing).

Main Results:

• Rapamycin and temsirolimus were found to induce UPR in sarcoma cells.
• The UPR induction was associated with drug binding to ribosomes, suggesting a mechanism independent of classical mTOR inhibition.
• Temsirolimus protected specific rRNA residues from chemical modification.
• Maximum tumor cell growth inhibition was observed at doses that induced UPR and are safely achievable in patients.

Conclusions:

• mTOR inhibitors can induce UPR through mechanisms potentially involving ribosome binding, distinct from direct mTOR inhibition.
• UPR activation correlates with enhanced anti-cancer efficacy of rapamycin and rapalogs.
• eIF2 alpha phosphorylation and Xbp-1 splicing may serve as predictive biomarkers for patient response to these therapies.