A circadian component to cancer?

Disruption in circadian rhythms might be implicated in other unexpected disease areas, too, like diabetes and sepsis

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LA JOLLA, Calif.—A growing body of research has suggested a connection between disruption in circadian rhythms, such as frequent jet-lag and shift work, and a wide range of medical conditions like diabetes, sepsis, and cancer. In a study published in November in the journal Molecular Cell, a team led by scientists at The Scripps Research Institute (TSRI) describe their discovery of an role for a protein in the connection between circadian clocks and cancer.
The researchers focused their attention on cryptochrome proteins, called CRY1 and CRY2, which are derived from bacterial proteins that sense light and repair DNA damage caused by sunlight. In mammals these are responsible for the development and regulation of circadian rhythms, which influence, among other things, hunger and wake-sleep cycles.
Using cells from mouse models, the scientists showed that, if the gene which expresses CRY2 is deleted, the cells were unable to degrade the protein cMYC, which is linked to cancer. Without CRY2 to keep the cMYC protein at normal levels, the researchers saw a proliferation of cells like the abnormal growth seen in cancers.
“This appears to have big implications for the connection between circadian rhythms and cancer,” said TSRI biologist Katja Lamia, senior author of the study.
The authors point out that CRY1 cannot substitute for CRY2 in promoting cMYC proliferation. “Their unique functions,” they write, “may explain prior conflicting reports that have fueled uncertainty about the relationship between clocks and cancer. We demonstrate that c-MYC is a target of CRY2-dependent protein turnover, suggesting a molecular mechanism for circadian control of cell growth and a new paradigm for circadian protein degradation.”
Further studies of protein structures suggested that CRY2 is a key player in a process to “mark” cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription—once the proteins are already produced—rather than during transcription, as in many other cryptochrome functions.
“This is a function of a circadian protein that has never been seen before,” said Anne-Laure Huber, a TSRI research associate who served as first author of the study.
The scientists say that additional studies are still needed to confirm the connection between disruptions in the circadian rhythms and cancer. DDNews was unable to obtain a response from TSRI researchers as to what degree—should this research continue to bear out—that circadian cycles might need to be factored into issues like selection and monitoring of lab animals in preclinical oncology efforts and humans in clinical trials, or even in issues such as precision medicine efforts and making sure the right patients (in the right physiological state) are matched with the right drugs.
The study, “CRY2 and FBXL3 Cooperatively Degrade c-MYC,” was published in the November 2016 issue of Molecular Cell.
In other recent news from TSRI on the R&D front—in a completely other therapeutic area—a new study led by scientists at TSRI is the first to show exactly how the drug Arbidol stops influenza infections. The research reveals that Arbidol stops the virus from entering host cells by binding within a recessed pocket on the virus.
The researchers believe this new structural insight could guide the development of future broad-spectrum therapeutics that would be even more potent against influenza virus.
“This is a very interesting molecule, and now we know where it binds and precisely how it works,” said study senior author Ian Wilson, Hanson Professor of Structural Biology, chair of the Department of Integrative Structural and Computational Biology and member of the Skaggs Institute for Chemical Biology at TSRI.
The study was published in the journal Proceedings of the National Academy of Sciences.
Arbidol is an antiflu treatment sold in Russia and China by the Russian pharmaceutical company Pharmstandard; the drug is currently in clinical trials in the United States. The drug targets many strains of influenza, giving it an advantage over seasonal vaccines that target only a handful of strains. The new study sheds light on exactly how it accomplishes this feat.
Scientists had long been curious whether Arbidol bound to the viral proteins used to recognize host cells—or with the viral “fusion machinery” that enters and infects host cells. To answer this question, the researchers used X-ray crystallography to create 3D structures showing how Arbidol binds to two different strains of influenza virus.
The structures revealed that Arbidol binds to the virus’s fusion machinery, as some had suspected. The small molecule binds to a viral protein called hemagglutinin, stopping the virus from rearranging its conformation in a way that enables the virus to fuse its membrane with a host cell.
“We found that the small molecule binds to a hidden pocket in hemagglutinin,” said study first author Rameshwar U. Kadam, senior research associate at TSRI. He added that the drug acts as a sort of “glue” to hold the subunits of hemagglutinin together. “Arbidol is the first influenza treatment shown to use a hemagglutinin-binding approach,” he said.
This vulnerable pocket is “conserved,” meaning it is likely important for viral function—and more difficult to mutate as the virus spreads—suggesting why Arbidol has relatively broad use in fighting many strains of the virus, including emerging strains.
The new findings also help scientists understand how Arbidol compares to influenza treatments such as Tamiflu. Wilson explained that Tamiflu prevents the virus from getting out of cells, while Arbidol prevents it from getting in. This means Arbidol, or future drugs that take a similar approach, could be given as a preventative treatment before an outbreak hits.
Wilson said the next step for researchers is to discover and/or design other small molecule therapeutics that can bind even more tightly with the hemagglutinin.

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