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Skp2 activates cancer-promoting, glucose-processing Akt
Date:5/25/2012

it must move from the cytosol to the plasma membrane. To do that, Lin and colleagues had previously shown that Akt must be ubiquitinated and those ubiquitins must be attached in a specific chain formation, the K63-linked polyubiquitin chains.

That earlier finding involved the insulin-like growth factor receptor (IGF-1) and a different E3 ligase. "Finding that the epidermal growth factor receptors also ubiquitinate Akt, and that they do so through the Skp2 E3 ligase, was quite unexpected," Lin said.

Finding two paths to ubiquitination implies that there might be more, Lin said.

Regulating cancer's energy engine

Tumor cells evolve to rely mainly on glucose processing to generate energy, grow and thrive. They increase glucose uptake and glycolysis, a process that doesn't involve oxygen and occurs in the cell's cytosol. Non-cancerous cells rely more heavily on oxygen-based metabolism of fatty acids and other nutrients in the cell's mitochondria. This difference is called the Warburg Effect.

In a series of experiments, the researchers blocked Skp2 expression and found:

  • Suppression of glucose uptake and glycolysis in breast cancer cell lines.
  • Reduction of tumor size and glucose uptake in a mouse model of HER2-expressing breast cancer.
  • Steep declines in the expression of glucose-transporter Glut1. Cells with Skp2 produced more Glut1 when induced by epidermal growth factor signaling. Akt activates Glut1.
  • Reduced Akt activation, Glut1 expression and tumor growth plus extended survival in mice genetically engineered to develop breast cancer and metastasis.

Poor prognosis, Herceptin resistance

The team analyzed 213 cases of breast cancer treated with modified radical mastectomy but no chemotherapy or radiation. Of these, 80 were HER2-positive. In these tumors Skp2 expression was correlated with:

  • Adverse prognostic factors such as cancer
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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