04:12pm Friday 15 December 2017

Long Sought Cancer Target Unraveled

Researchers have discovered a small molecule that disables a prized cancer target, one that many pharmaceutical and biotech companies have been investigating for years.

The findings, which also establish a chain linking the target to the tumor-suppressing gene p53, suggest a long-sought weapon against the defenses of cancer cells.

The results were published in the journal Cell.

The cancer target is a complex that regulates the formation of autophagsomes in the cell’s cytoplasm. Autophagosomes are lipid vesicles that function to dispose of old proteins and expired organelles. Like the B-movie monster “The Blob,” they wrap themselves around cellular garbage and degrade the material with hydrolytic enzymes.

The process, called autophagy, rids cells of debris and is crucial for cell survival.

“Autophagy helps cells survive stress,” said Junying Yuan, Harvard Medical School professor of cell biology and senior author on the paper. “It’s like a recycling process that degrades old proteins into amino acid energy sources enabling cells to survive in difficult circumstances. It’s a turnover mechanism.”

When autophagy falters, life span shortens, and cancer and other diseases, such as neurodegeneration, can ensue. One such defect, in a gene called Beclin1, decreases autophagy in mammalian cells, and researchers have suspected that this leads to increased prostate and breast cancers.

But like so many cancer factors, autophagy can be a double-edged sword.

When a patient is undergoing treatment such as chemotherapy, cancer cells co-opt autophagy and use it to survive the stress of therapy. Researchers have reasoned that in certain clinical settings, briefly disabling autophagy may support and enhance treatment.

For years, pharmaceutical companies have sought to do just that. The challenge lay in identifying the precise target within a protein complex. Yuan and her colleagues developed a cell-based screening platform in which they uncovered a key mechanism of autophagy as well as a small molecule that efficiently blocks the process by degrading the protein complex that autophagy depends on. The protein beclin1, encoded by the Beclin1 gene already linked to autophagy, is a part of this complex.

They named the molecule spautin-1, for specific and potent autophagy inhibitor-1.

Drilling deeper, the researchers found that spautin-1 blocked the activity of USP10, a molecule that offers a kind of “stay of execution” for proteins on death row. Proteins marked for disposal are tagged with a marker called ubiquitin, and USP10 often removes this tag from select proteins, sparing them. Removing USP10 leaves these proteins vulnerable.

Beclin1, it turns out, regulates the activity of USP10. And the researchers connected these findings to other studies linking USP10 to p53, a gene widely known to suppress cancer.

“Knocking down Beclin1, which our small molecule does, knocks down USP10, which in turn knocks down p53,” said Yuan. “They are all part of a chain.”

This then explains the earlier observation that mammals with defective Beclin1 experience increased cancer. When beclin1 is diminished, p53, which is downstream, is also diminished, and cancer thrives. However, when Beclin1 is removed altogether, the cell dies. This discovery? suggests that selectively targeting autophagy during cancer therapies may greatly benefit patients.

Yuan is now collaborating with researchers at the company Roche, based in Basel, Switzerland and at BioBay, based in Suzhou, China, to translate these findings into potential therapies.

This research was funded by the National Institutes of Health, the Chinese Academy of Sciences, the National Natural Science Foundation of China, and the Harvard University Biomedical Accelerator Fund.

—David Cameron


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