Interactome Analysis of Microtubule-targeting Agents Reveals Cytotoxicity Bases in Normal Cells

Area of Science:

• Oncology
• Molecular Biology
• Systems Biology

Background:

• Microtubule-targeting agents (MTAs) are crucial in cancer therapy but exhibit significant toxicity to normal cells.
• The non-specific targeting of MTAs necessitates understanding their interactions within non-cancerous cells.

Purpose of the Study:

• To analyze the interaction network of MTAs in a non-cancerous human cell.
• To identify shared targets and affected cellular processes.
• To investigate potential reasons for MTA-induced toxicity and synergistic effects.

Main Methods:

• Reconstruction of subnetworks for fourteen MTAs.
• Comparison of the merged MTA interactome network against a randomized network.
• Identification of client proteins of interphase microtubules as potential secondary targets.

Main Results:

• 71.4% of MTA interactome nodes are shared across different agents, impacting key cellular processes like apoptosis, cell differentiation, cell cycle control, stress response, and energy metabolism.
• Client proteins of interphase microtubules were identified as potential secondary targets for MTAs.
• Paclitaxel and doxorubicin networks share topological axes, indicating potential synergistic interactions.

Conclusions:

• MTAs primarily target non-tumor cells by interacting with client proteins of interphase microtubules, contributing to their toxicity.
• The shared topological features between paclitaxel and doxorubicin networks may explain the severe toxicity observed in combination therapies.