Autophagy regulates Selumetinib (AZD6244) induced-apoptosis in colorectal cancer cells

• Selumetinib induces cell death and autophagy blockage in SW480 CRC cell line.
• Autophagy induction decreases Selumetinib effectiveness.
• Autophagy inhibition increased Selumetinib-induced cell death in CRC cells.
• Autophagy inhibition may be a useful strategy to enhance Selumetinib activity.

ObjectiveAs Selumetinib is a MEK1/2 inhibitor that has gained interest as an anti-tumor agent, the present study was designed to investigate autophagy involvement on Selumetinib-induced apoptosis in colorectal cancer (CRC) cells.MethodsCRC cells death and cycle studies were assessed by AnnexinV-FITC and PI staining, respectively. Autophagy flux was analysed by Western Blot (LC3II and p62 protein levels) and retroviral infection of SW480 cells for siBecn1 RNA interference experiments. Confocal microscopy was used to determine mCherry-EGFP–LC3 distribution.Key findingsThe Selumetinib effects were concentration-dependent in SW480 cell line. Whereas 1 μM exerted an arrest in the cell cycle (G1 phase), higher concentrations (10 μM) induced cell death, which was accompanied by autophagy blockage in its last stages. Autophagy induction by Rapamycin (RAPA) increased cell survival, whereas pharmacology autophagy inhibition by Bafilomycin A1 (BAF), Chloroquine (CQ) or 3-Methyladenine (3-MA) increased Selumetinib-induced CRC cells death.ConclusionsAltogether, these results suggest that autophagy plays a fundamental role in CRC cells response to Selumetinib. In addition, the combination of Selumetinib with autophagy inhibitors may be a useful therapeutic strategy to enhance its activity against colorectal tumours.

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