A New Pathway

Topic: A New Pathway To Kill Resistant Breast Cancer

As all the recent news about protein folding should make clear, there are a lot of ways for any given protein sequence to come together into a three-dimensional structure. For that phrase “a lot”, substitute “a larger number than the human mind can possibly comprehend”, and you’ll be about right. Biologically, many proteins already display a bias towards folding in the correct manner, and they’re helped along in many cases by so-called “chaperone” proteins. This sort of thing happens constantly in the endoplasmic reticulum (ER) structure of the cell, where ribosomes sit and extrude their nascent polypeptide chains. Chaperone proteins recognize common structural features and folds, and guide the developing protein into familar territory.

Things don’t always work out. Various sorts of cellular stress can disturb the ER, with a rise in unfolded and misfolded proteins. There’s an emergency system that kicks in when this happens, the “unfolded protein response” (UPR). That’s a whole program that attempts to get things back to normal by increasing the amounts of chaperone proteins, slowing protein translation down in general to give things a chance to catch up, and degrading the unrecoverable misfolded species. If none of these work, the UPR starts activating apoptosis pathways, directing the cell to destroy itself rather than continue in this state.

This is all good and necessary stuff. But all the swords in cell biology have two edges. In diseases characterized by constantly aggregated proteins (Huntington’s, Parkinson’s, prion diseases and more) the UPR can be running so high and so constantly that it causes trouble of its own. The same situation occurs in breast cancer (among other types), where an always-on UPR seems to make tumor cells even more resistant and vigorous than they would be otherwise. There have been several drug discovery programs targeted at inhibiting one part or another of the UPR, but there’s a new paper that takes the opposite approach: it turns on the UPR even harder in hopes of finally kicking in that apoptosis signaling waiting at the end of it.

Topic Discussed: A New Pathway To Kill Resistant Breast Cancer

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