The “cargo carriers,” or endosomes, of certain brain cancer cells contain overactive NHE9 proteins (blue), which pump out too many protons (orange), changing the endosomes’ acidity and slowing their “shipping speed.” Credit: Hari Prasad & Rajini Rao
Both Autism and Brain Cancer disorders involve faults in the same protein associated with excess acidity!
A summary of their work in human tumor cells and mice is published in the journal Nature Communications .
All animal and human cells contain many “cargo packages” surrounded by membranes. These so-called endosomes carry newly minted proteins to specific destinations throughout the cell and haul away old proteins for destruction. Key to their “shipping speed” is the level of increased acidity inside the endosomes. This is controlled by balancing the activity of protein “pumps” that push protons into endosomes to increase their acidity with that of protein “leaks,” like NHE9, that remove protons.
Rao says: “Endosomes are like buckets of water that have to be kept full despite the leaks in them. Altering either the faucet or the leak rate can dramatically change the water level in the bucket.”
As they suspected, the team found that alkaline endosomes slow down the removal of EGFR from cell surfaces. Lab-grown tumor cells were more readily killed when treated with both a drug countering NHE proteins and a drug against EGFR than when treated by the EGFR-targeting drug alone.
Quinones-Hinojosa says: “We are still five to 10 years away from testing this idea in patients, but these results are encouraging. They give us a better idea of what to target so that hopefully we can make this disease less aggressive and less devastating.”
Kalyan C. Kondapalli, Jose P. Llongueras, Vivian Capilla-González, Hari Prasad, Anniesha Hack, Christopher Smith, Hugo Guerrero-Cázares, Alfredo Quiñones-Hinojosa, Rajini Rao. A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma. Nature Communications, Published February 9 2015. doi: 10.1038/ncomms7289
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