Photo by Andre Karwath
New research has revealed a mechanism that allows cancer cells to respond and grow rapidly when blood sugar levels rise.
This may help to explain why people who develop conditions in which they have chronically high blood sugar levels, such as obesity, also have an increased risk of developing certain cancers.
Susumu Hirabayashi, PhD, of Imperial College London in the UK, and Ross Cagan, PhD, of Mount Sinai Hospital in New York, New York, described the mechanism in eLife.
In a study published 2 years ago, the pair engineered fruit flies (Drosophila melanogaster) to activate the genes Ras and Src, which are activated in a range of malignancies.
The researchers activated Ras and Src in the flies’ developing eye tissue. Flies that were fed a normal diet grew small, benign tumors. But when flies were fed a high-sugar diet, they developed large, malignant tumors.
In flies fed a high-sugar diet, the normal cells became insulin-resistant, but the tumor cells didn’t. The tumor cells actually became more sensitive to insulin because they turned on a metabolic switch that triggered them to produce extra receptors for insulin. But this study did not explain how the tumor cells turned on this metabolic switch.
Now, after studying the same flies in more detail, Drs Hirabayashi and Cagan have found the tumor cells detect glucose availability indirectly, through a protein called salt-inducible kinase (SIK). When glucose levels are high, SIK sends a signal along the Hippo signaling pathway.
The Hippo signaling pathway is known to play a role in controlling cell growth. When it’s turned on, it keeps cell growth under control, but if it’s turned off, the cell can continue growing and may ultimately develop into a tumor.
Drs Hirabayashi and Cagan found that SIK acts like a sugar sensor, turning the Hippo signaling pathway off in response to raised glucose levels. This allows the tumor cells to continue to grow.
“Ras and Src co-activated tumors use SIK to sense that there’s lots of glucose available outside of their cells and to tell the cells to take advantage of that,” Dr Hirabayashi said. “Together, Ras and Src co-activated tumors use SIK to efficiently respond to glucose availability and ensure the tumors grow in nutrient-rich conditions such as obesity. We still don’t know if tumors caused by other genes respond to sugar in the same way.”
“Our results suggest that if we can develop drugs to target SIK, and stop it from alerting cancer cells in this way, then we may be able to stop cancer cells from thriving in an insulin-resistant environment and break the connection between obesity and cancer.”
