Killing cancer by clogging its garbage disposal system

Beating cancer in all its forms isn’t likely to come from a single “eureka!” moment, but numerous little advances and new techniques that add up to better treatments. Whether we zap tumors, starve them out or develop treatments from sources like sea snail eggs or artificial sweeteners, cancer could succumb to death by a million cuts. The newest little cut could come from interrupting the natural waste disposal system of cells, causing defective proteins to build up and choke the cancer cells out.

No one can be expected to work at the top of their game 100 percent of the time, and cells making proteins are no different. Sometimes proteins fail to fold properly, and when they do, cells recycle them through a cylindrical structure called a proteasome – basically, a cellular garbage disposal. Defective proteins are tagged for destruction by a repeating chain of small proteins called ubiquitin, and these duds are fed into one end of the proteasome, minced up and released as fragments of amino acids, which the cell can then reuse to make new proteins.

As part of this process, an enzyme called Rpn11 sits at the mouth of the proteasome and chops the ubiquitin chain into smaller segments, to make sure it fits inside the proteasome. This vital enzyme is the target for the new research, which involved the development of a compound that inhibits Rpn11’s ability to function. That makes the proteasome far less effective at disposing of bad proteins, causing the garbage to pile up and stressing the cancer cell to death.

The fluorescent green spots are blobs of dysfunctional proteins building up on cancer cells, as a...

The fluorescent green spots are blobs of dysfunctional proteins building up on cancer cells, as a result of the new treatment(Credit: Deshaies Lab)

There’s a slight hitch though: the team’s new compound doesn’t single out cancer, meaning the treatment will interrupt the cleanup processes of healthy and unhealthy cells alike. But, the researchers point out, healthy cells make far fewer mistakes during protein production, so cancer cells are more sensitive to the treatment and will only require a small dose to be killed.

Targeting the proteasome isn’t an entirely new strategy for fighting cancer, but existing drugs focus on different enzymes in the structure, and are reportedly less effective, with patients often either not responding to the treatment, or suffering a relapse later on.

“All current cancer drugs that target the proteasome work by inhibiting the protein-chopping enzymes on the inside of the proteasome; therefore they all have similar drawbacks and tend to lose efficacy over time,” says Jing Li, first author of the study. “Our research offers an alternative path to disabling proteasome function, including in cells that no longer respond to the existing drugs.”

While the team has so far only tested the compound on human cancer cells in a laboratory setting, the next step is to study ways to make the compound more effective, before beginning animal testing.

The research was published in the journal Nature Chemical Biology.

Source: Caltech

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