Transcript 대사조절론 05.27 김한얼.

Gain of Glucose-Independent Growth upon
Metastasis of Breast Cancer Cells to the Brain
김한얼
Introduction
<Breast Cancer Cell Line>
 MDA-MB-231
- Origin : breast, mammary gland
- Species : human
 MDA-MB-231 Br3
- nude mouse에서 MDA-MB-231 접종 후 뇌 전이된 세포주
 MDA-MB-361
- breast cancer cell line isolated from human brain metastasis
 4T1
- breast cancer cell line
- Species : Mus musculus, mouse
<Breast Cancer Brain Metastasis>
 유방암은 여러 기관으로 전이 가능하며 뼈로의 전이가 빈번함.
 유방암 환자에서 암 전이는 사망률을 높이는 주된 원인임.
 약 10%의 유방암 환자에서 뇌 전이가 관찰됨.
 유방암 전이의 생존율은 국부적 침윤에서 98.1%, 먼 거리의 전이는 26%의 낮
은 생존율을 보임.
<Breast cancer brain metastases>
In this study
 유방암의 뇌 전이는 빈번하게 발생.
 전이된 암세포는 흔히 변형된 대사를 가짐으로써 높은 성장과 생존을 보임.
 변형된 대사를 초점으로 하여 암 치료의 수단으로써 사용.
Results
Figure 1. MDA-MB-231Br3 cells proliferate in the absence of glucose.
Figure 2. Glutamine and BCAAs are needed for the glucose independent survival of MDA-MB-231Br3 cells.
GLUD : glutamate Dehydrogenase
Figure 2. Glutamine and BCAAs are needed for the glucose independent survival of MDA-MB-231Br3 cells.
BCKDH-E1 : branched-chain ketoacid dehydrogenase E1
BDK : branched chain ketoacid dehydrogenase kinase
pSer293-BCDKH-E1 : inactivated form of BCKDH-E1
(phosphorylated at serine 293 of the E1 subunit)
Figure 3. Gluconeogenic fructose-1,6-bisphosphatase 2 is upregulated in MDA-MB-231Br3 cells.
PEPCK1 : phosphoenylpyruvate carboxykinases
FBP : fructose-1,6-bisphosphatase
Figure 4. MDA-MB-361 cells exhibit glucose-independent phenotypes similar to the MDA-MB-231Br3 cells
PEPCK1 : phosphoenylpyruvate carboxykinases
FBP : fructose-1,6-bisphosphatase
BCKDH-E1 : branched-chain ketoacid dehydrogenase E1
BDK : branched chain ketoacid dehydrogenase kinase
pSer293-BCDKH-E1 : inactivated form of BCKDH-E1
(phosphorylated at serine 293 of the E1 subunit)
GLUD : glutamate Dehydrogenase
Figure 5. Metabolic characterization of brain metastatic breast cancer cells upon glucose deprivation
Figure 5. Metabolic characterization of brain metastatic breast cancer cells upon glucose deprivation
PEP : phosphoenolpyruvate
GAP : glyceraldehydes-phosphate
Figure 6. FBP2 is upregulated in breast cancer brain metastasis
Figure 6. FBP2 is upregulated in breast cancer brain metastasis
Figure 7. Knocking down FBPs prolonged survival of immunocompetent mice bearing orthotopic
breast cancer brain metastasis
MFP : mammary fat pad
Figure 7. Knocking down FBPs prolonged survival of immunocompetent mice bearing orthotopic
breast cancer brain metastasis
Discussion
 Breast cancer brain metastatic cells can utilize gluconeogenesis and oxidation of BCAAs
for growth independent of glucose, which is important for the growth of breast cancer
brain metastasis in vivo.
 Targeting amino-acid–dependent gluconeogenesis may be a novel approach for the
treatment of fatal brain metastasis.