Cancer cells need a lot of nutrients to multiply and
survive. While much is understood about how cancer cells
use blood sugar to make energy, not much is known about how
they get other nutrients. Now, researchers at the Johns
Hopkins University School of Medicine have discovered how
the Myc cancer-promoting gene uses microRNAs to control the
use of glutamine, a major energy source. The results, which
shed light on a new angle of cancer that might help
scientists figure out a way to stop the disease, appeared
Feb. 15 online at Nature.
"While we were looking for how Myc promotes cancer growth,
it was unexpected to find that Myc can increase use of
glutamine by cancer cells," said Chi V. Dang, the Johns Hopkins Family
Professor of Oncology at Johns Hopkins. "This surprising
discovery only came about after scientists from several
disciplines came together across Hopkins to collaborate
— it was a real team effort."
In their search to learn how Myc promotes cancer, the
researchers teamed up with protein experts, and using human
cancer cells with Myc turned on or off they looked for
proteins in the cell's powerhouse — the mitochondria
— that appeared to respond to Myc. They found eight
proteins that were distinctly turned up in response to
Myc.
At the top of the list of mitochondrial proteins that
respond to Myc was glutaminase, or GLS, which, according to
Dang, is the first enzyme that processes glutamine and
feeds chemical reactions that make cellular energy. So the
team then asked if removing GLS could stop or slow cancer
cell growth. Compared to cancer cells with GLS, those
lacking GLS grew much slower, an outcome that led the team
to conclude that yes, GLS does affect cell growth
stimulated by Myc.
The researchers then wanted to figure out how Myc enhances
GLS protein expression. Because Myc can control and turn on
genes, the team members guessed that Myc might directly
turn on the GLS gene, but they found that wasn't the case.
"So then we thought, maybe there's an intermediary; maybe
Myc controls something that in turn controls GLS," said
Ping Gao, a research associate in hematology at Johns
Hopkins.
They then built on previous work done with the
McKusick-Nathans Institute of Genetic Medicine at Johns
Hopkins, where they discovered that Myc turns down some
microRNAs, small bits of RNA that can bind to and inhibit
RNAs, which contain instructions for making proteins. The
team looked more carefully at the GLS RNA and found that it
could be bound and regulated by two microRNAs, called
miR23a and miR23b, pointing to the microRNAs as the
intermediary that links Myc to GLS expression.
"Next we want to study GLS in mice to see if removing it
can slow or stop cancer growth," Gao said. "If we know how
cancer cells differ from normal cells in how they make
energy and use nutrients, we can identify new pathways to
target for designing drugs with fewer side effects."
This study was funded by the National Institutes of Health,
National Cancer Institute, Rita Allen Foundation, Leukemia
and Lymphoma Society and Sol Goldman Center for Pancreatic
Cancer Research.
Authors on the paper are Gao, Irina Tchernyshyov,
Tsung-Cheng Chang, Yun-Sil Lee, Karen Zeller, Angelo De
Marzo, Jennifer Van Eyk, Joshua Mendell and Dang, all of
Johns Hopkins; and Kayoko Kita and Takfumi Ochi, both of
Teikyo University in Japan.