Cancer Cells Gain Survival Advantage by Blocking Proautophagic MicroRNA

By increasing the activity of the mechanism that controls autophagy cancer cells create a large pool of molecular building blocks, which gives them a growth and survival advantage over the cells in normal tissues.

Investigators at the Biotech Research and Innovation Center of the University of Copenhagen (Denmark) conducted a series of experiments to unveil the molecular mechanism that allows cancer cells to enhance their ability to reprocess unneeded proteins.

They reported in the September 13, 2011, online edition of EMBO Journal that cancer cells increased their autophagic ability by blocking the activity of the tumor suppressive microRNA (miRNA), miR-101, a potent inhibitor of basal, etoposide- and rapamycin-induced autophagy. Normally miR-101 targets a group of genes including, STMN1, RAB5A and ATG4D. siRNA-mediated depletion of these genes caused an effect identical to miR-101 overexpression, demonstrating their importance in autophagy regulation.

Overexpression of STMN1 could partially rescue cancer cells from miR-101-mediated inhibition of autophagy. Breast cancer cells where miR-101-mediated inhibition of autophagy was active were more sensitive to 4-hydroxytamoxifen (4-OHT)-mediated cell death than were cells where miR-101 was blocked.

"We have discovered a small molecule that can block autophagy in different cancer cells and specifically, this molecule can increase the sensitivity of breast cancer cells towards one of the most commonly used treatments for breast cancer," said senior author Dr. Anders H. Lund, professor at the Biotech Research and Innovation Center of the University of Copenhagen. "This result has a clear clinical relevance, as resistance against tamoxifen is a large problem in the treatment of breast cancer."

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Biotech Research and Innovation Center of the University of Copenhagen