Reports
Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells
Jihye Yun 1, Carlo Rago 1, Ian Cheong 1, Ray Pagliarini 2, Philipp Angenendt 1, Harith Rajagopalan 3, Kerstin Schmidt 1, James K. V. Wilson 4, Sandy Markowitz 5, Shibin Zhou 1, Luis A. Diaz Jr.1, Victor Velculescu 1, Christoph Lengauer 6, Kenneth W. Kinzler 1, Bert Vogelstein 1*, Nickolas Papadopoulos 1
Tumor progression is driven by genetic mutations, but little
is known about the environmental conditions that select for
these mutations. Studying the transcriptomes of paired colorectal
cancer cell lines that differed only in the mutational status
of their
KRAS or
BRAF genes, we found that
GLUT1, encoding glucose
transporter-1, was one of three genes consistently upregulated
in cells with
KRAS or
BRAF mutations. The mutant cells exhibited
enhanced glucose uptake and glycolysis and survived in low glucose
conditions, phenotypes that all required
GLUT1 expression. In
contrast, when cells with wild-type
KRAS alleles were subjected
to a low glucose environment, very few cells survived. Most
surviving cells expressed high levels of GLUT1, and 4% of these
survivors had acquired new
KRAS mutations. The glycolysis inhibitor
3-bromopyruvate preferentially suppressed the growth of cells
with
KRAS or
BRAF mutations. Together, these data suggest that
glucose deprivation can drive the acquisition of
KRAS pathway
mutations in human tumors.
KRAS or BRAF の相互排他的変異がともに影響を受ける(rasだけではないというのがミソのような気がする)とすれば、面白い。
低血糖のほうが不利なのか。疫学的には大腸癌に糖尿病は危険因子ではなかったけ・・・??原本を読んでみたいな。
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