Cancers' sweet tooth may be weakness
http://www.physorg.com/news177769436.html
November 18th, 2009 in Medicine & Health / Cancer
The pedal-to-the-metal signals driving the growth of several types of cancer cells lead to a common switch governing the use of glucose, researchers at Winship Cancer Institute of Emory University have discovered.
Scientists who study cancer have known for decades that cancer cells tend to consume more
glucose, or blood sugar, than healthy cells. This tendency is known as the "Warburg effect," honoring discoverer Otto Warburg, a German biochemist who won the 1931
Nobel Prize in Medicine. Now a Winship-led team has identified a way to possibly exploit cancer cells' taste for glucose.
The results were published this week in the journal
Science Signaling.
Normally cells have two modes of burning glucose, comparable to sprinting and long-distance running: glycolysis, which doesn't require oxygen and doesn't consume all of the glucose molecule, and oxidative phosphorylation, which requires oxygen and is more thorough.
Cancer cells often outgrow their blood supply, leading to a lack of oxygen in a tumor, says Jing Chen, PhD, assistant professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. They also benefit from glycolysis because leftovers from the inefficient consumption of glucose can be used as building blocks for growing cells.
"Even if they have oxygen, cancer cells still prefer glycolysis," Chen says. "They depend on it to grow quickly."
Working with Chen, postdoctoral researcher
Taro Hitosugi focused on the enzyme PKM2 (pyruvate kinase M2), which governs the use of glucose and controls whether cells make the switch between glycolysis and oxidative phosphorylation. PKM2 is found predominantly in fetal cells and in
tumor cells.
In many types of cancer, mutations lead to over-activation of proteins called tyrosine kinases. Chen's team showed that tyrosine kinases turn off PKM2 in lung, breast, prostate and blood cancers. Introducing a form of PKM2 that is not sensitive to tyrosine kinases into
cancer cells forces them to grow slower and be more dependent on oxygen, they found.
Because the active form of PKM2 consists of four protein molecules stuck together, having a tyrosine kinase flip the "off" switch on one molecule can dampen the activity for the others.
"People knew that tyrosine kinases might modify PKM2 for decades but they didn't think it mattered," Chen says. "We showed that such a modification is important and you even don't need that much modification of PKM2 to make a difference in the cells' metabolism."
PKM2 could be a good drug target, because both inhibiting it or activating it can slow down cancer cell growth. Biotechnology companies are already searching for ways to do so, Chen says.
More information: T. Hitosugi et al. Tyrosine phosphorylation inhibits PKM2 to promote the Wargurg effect and tumor growth. Sci. Signal. 2, ra73 (2009).
Source: Emory University (
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http://www.physorg.com/news177769436.html
[1133] Metformin Enhances Trastuzumab Efficacy and Overcomes Resistance in HER2 Type Breast Cancer Cells.
Thor AD, Fan Z, Yang X-H, Esteva FJ, Jones FE, Edgerton SM, Lind SE, Liu B University of Colorado Denver, Aurora, CO; University of Oklahoma Health Sciences Center, Oklahoma City, OK; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Tulane University, New Orleans, LA
Background: HER2 alterations occur in one-fourth of breast cancers and are associated with an aggressive tumor phenotype. The anti-HER2 agent trastuzumab reduces cell proliferation, angiogenesis, DNA repair and induces antibody-dependent cellular cytotoxicity. Objective response rates and median duration of response for eligible patients given trastuzumab alone is low (12-34% and 9 months respectively), hence, it is administered in combination with other agents. Mechanisms of trastuzumab resistance include: altered receptor antibody interactions, increased signaling through other EGFR type I growth factor receptors, modulation of p27
kip1 and increased insulin-like growth factor 1 receptor (IGF-1) signaling. We have reported that metformin inhibits HER2 expression, tyrosine kinase activity (phosphorylated HER2 at both auto- and Src- phosphorylation sites), AKT/mTOR signaling, Cyclin D1 and E2F1 with G1 arrest in HER2 overexpressing breast cancer cells. We sought to determine if metformin would enhance trastuzumab associated cytotoxicity and modulate acquired resistance in vitro.
Methods: We used trastuzumab sensitive (SKBR3, BT474) and resistant cell lines (BT-474/HR20, SKBR3/P2, MCF-7/713 and MCF-7/HER2Δ16) to study the effects of metformin, metformin + trastuzumab and trastuzumab alone. Assays included MTS for proliferation, clonogenicity studies, Western blots, and pull down experiments with Western blots.
Results: Trastuzumab sensitive breast cancer cells were less sensitive to metformin alone, compared to trastuzumab resistant HER2 subtype breast cancer cell lines. Trastuzumab sensitive cells showed enhanced growth and clonogenicity inhibition when treated by both metformin and trastuzumab. At the molecular level, these bi-treated cells showed decreases in HER2/pHER2, erbB3/perbB3, and inactivation of AKT and MAPk signaling. Metformin as low as 20mM increased the efficacy of trastuzumab. All HER2 resistant cell lines showed higher levels of IGF1R and HER2/IGF1R complexes, as compared to sensitive parental lines. In these resistant lines Metformin decreased cell proliferation and clonogenicity, HER2/IGF1R complexes (identified through pull down experiments) and protein expression of HER2/pHER2, erbB3/perbB3, IGF1R/pIGF1R as well as downstream signaling via Akt and IGF1 pathways. Metformin overcame trastuzumab resistance as demonstrated by growth and clonogenicity assays.
Conclusions: HER2 amplified trastuzumab resistant breast cancer cells showed greater sensitivity to metformin than sensitive parental lines. Metformin reversed trastuzumab resistance and decreased HER2:IGF1R complexes, HER2/pHER2 and IGF1R expression, whereas sensitive parental lines showed no complex formation. These preclinical data suggest a combination of metformin and trastuzumab may have clinical benefit, improving the efficacy and reducing the emergence of or reversing trastuzumab resistance in HER2 positive breast cancer patients.
Herceptin graciously provided by Genentech
Thursday, December 10, 2009 5:30 PM
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