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UCLA-Led Study IDs Kinase Signaling Feedback Loop Linked to Cell Death in Glucose-Dependent Cancers

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University of California, Los Angeles researchers have demonstrated that glucose starvation in cancer cells can activate a positive feedback loop that heightens levels of tyrosine phosphorylation and leads to cell death.

Detailed in a paper published this week in Molecular Systems Biology, the study identifies a potential mechanism by which glucose withdrawal causes cell death and suggests possible new targets for cancer treatment, Thomas Graeber, professor of molecular and medical pharmacology at UCLA and an author on the paper, told ProteoMonitor.

In particular, he said, it suggests that researchers and clinicians might look to attack cancer cells by increasing, rather than inhibiting, protein signaling.

"Most of the [existing cancer] therapeutics that target signaling are kinase inhibitors that turn off signaling, and then the cells die due to the lack of required signaling," Graeber noted. "One of the ideas that comes out of this [study] … is the idea of attacking a cancer cell by amplifying what's going on [in terms of kinase signaling] and pushing it out of its comfort zone in that direction."

The researchers, Graeber said, were interested in crosstalk that has been observed between protein signaling and glucose dependence and so decided to look system-wide at changes in cancer cell signaling in response to glucose deprivation.

"A fair amount had been done on how signaling impacts metabolism," he said, "and so we approached this project by asking the opposite question: how might metabolism impact signaling?"

Using antibody-based phospho-tyrosine peptide enrichment followed by mass spec analysis on a Thermo Fisher Scientific LTQ Orbitrap instrument, the researchers discovered that glucose withdrawal leading to cell death induced a significant increase in tyrosine kinase signaling.

This finding was somewhat counter to what the researchers might have expected to find, noted Nicholas Graham, a post-doctoral fellow in Graeber's lab and first author on the paper.

"In general, people think of having high levels of tyrosine kinase phosphorylation as correlating with cell growth rather than cell death," he told ProteoMonitor.

Taking this observation as a starting point, the researchers investigated the mechanisms behind this unexpected increase in signaling, finding that glucose withdrawal leads to an increase in generation of reactive oxygen species by NADPH oxidase and mitochondria. These ROS, in turn, inhibit protein tyrosine phosphatases via oxidation, which leads to increased tyrosine kinase signaling. This increase in kinase signaling leads to a further increase in ROS production, establishing a positive feedback loop that ultimately results in cell death.

"In general it's believed that phosphatases are highly active and constantly repressing signaling, and this mechanism shows that when that phosphatase activity is perturbed by reactive oxygen species generation you can have highly increased levels of tyrosine kinase signaling," Graham said. "There may be additional mechanisms [causing the uptick in signaling], but we think that the phosphatase inhibition is the primary mechanism."

The UCLA team performed the analysis detailed in the MSB paper in cell lines derived from glioblastoma, sarcoma, and melanoma, and Graeber said he expected their findings to apply to a broad range of cancer types. "We haven't found a type of cancer where we didn't … tend to see some cells respond this way," he said. "So I think that trend would probably hold, with maybe a few exceptions."

The researchers now hope to further investigate what might be the signaling processes that make some cancer cells susceptible to death due to glucose deprivation.

"We still don't have a great understanding of why some cells are resistant and some cells are sensitive to this mechanism," Graeber said, "but we're trying to understand that because we believe the mechanism is quite general [across cancer types.]"

He noted that the research suggests potential therapeutic approaches that target cells on both a metabolic and signaling level.

"There are many ongoing efforts to target cancer cell metabolism because cancer cells generally utilize more glucose and other metabolic substrates like glutamine," he said. "We think the power of this study is in showing that if you could co-target another node with this mechanism – using, for example, a phosphatase inhibitor or tyrosine kinase activator in combination with some of these metabolic inhibitors, you would cause synergistic cell death."

Graeber added that the large number of kinases activated by the phenomenon and the multiple targets for activating the ROS-tyrosine kinase feedback loop suggest therapies exploiting this mechanism might prove less susceptible to the development of resistance.

"Cancer cells are very good at rewiring, so I don't want to not give them credit in that regard," he said. However, he noted, "so many different kinases are activated through this mechanism that it would be hard [for the cell] to inhibit all those kinases and prevent this kind of catastrophe from continuing on."

He added that "since we know we can initiate the [amplification] loop at different points, either with a phosphatase inhibitor or a ROS activator or metabolic changes, that could make it more difficult for the cell to prevent [the loop] from occurring."

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