TY - BOOK
T1 - Non-metabolic Function of PKM2 in the Progression of Lung Cancer and Pancreatic Cancer
AU - Yang, Yi-Chieh
PY - 2017
Y1 - 2017
N2 - Metabolic alteration is one of the hallmarks of cancer cells. In contrast to normal cells, cancer cells had been reported to highly rely on aerobic glycolysis even the oxygen concentration is sufficient. This phenomenon is also called “Warburg effect”. Pyruvate kinase isoenzyme M2 (PKM2) is one of the rate-limiting enzymes in the glycolysis process, which catalyzes PEP into ATP and pyruvate. In addition to the well-established metabolic function, PKM2 works as a protein kinase in cancer cells were revealed in the past years. Both metabolic and nonmetabolic functions of PKM2 provide the advantage for the growth of cancer cells.The secondary mutation of EGFR resulted in drug resistance is one of the most critical issues in lung cancer therapy. In the first part of this study, we report that PKM2 stabilizes mutant EGFR protein and sustain cell survival signaling in lung cancer cells. The depletion of PKM2 leads to proteasome degradation of EGFR and significantly inhibited the tumor growth of EGFR mutant cells in xenograft model. Mechanistically, PKM2 directly interacts with mutant EGFR and stabilize EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR is relied on dimeric PKM2, and the protein half-life of mutant EGFR was decreased when PKM2 was forced to form tetramer after treating activators. Clinical levels of PKM2 positively correlate with mutant EGFR expression and correlate with patient outcome.Most of solid tumors suffer from glucose limited since the less amounts of vessels into tumor core. In the second part of the study, we found the nuclear translocation of the glycolic key enzyme, PKM2, in response to glucose deprivation in cancer cells. We demonstrate that glucose deprivation stimulates the AMPK activation and results in the nuclear translocation of PKM2 through Ran protein. Nuclear PKM2 then binds with OCT4 to promote the expression of cancer stemness-related genes. Thus, the nuclear PKM2 is able to enrich the cancer stem cell population. Furthermore, the nuclear PKM2 promotes cancer metastasis in an orthotopic xenograft model. Our findings provide first evidence that the cytosolic nutrient sensor AMPK works as a cooperator to help PKM2 carry out its nonmetabolic function in nucleus, and that is necessary for repopulation of cancer cells against and adapt to the metabolic stress.These results reveal a previously undescribed non-glycolysis function of PKM2 in cytoplasm and nucleus, and that provide a novel insight for the scientists to develop the drugs which target on PKM2.
AB - Metabolic alteration is one of the hallmarks of cancer cells. In contrast to normal cells, cancer cells had been reported to highly rely on aerobic glycolysis even the oxygen concentration is sufficient. This phenomenon is also called “Warburg effect”. Pyruvate kinase isoenzyme M2 (PKM2) is one of the rate-limiting enzymes in the glycolysis process, which catalyzes PEP into ATP and pyruvate. In addition to the well-established metabolic function, PKM2 works as a protein kinase in cancer cells were revealed in the past years. Both metabolic and nonmetabolic functions of PKM2 provide the advantage for the growth of cancer cells.The secondary mutation of EGFR resulted in drug resistance is one of the most critical issues in lung cancer therapy. In the first part of this study, we report that PKM2 stabilizes mutant EGFR protein and sustain cell survival signaling in lung cancer cells. The depletion of PKM2 leads to proteasome degradation of EGFR and significantly inhibited the tumor growth of EGFR mutant cells in xenograft model. Mechanistically, PKM2 directly interacts with mutant EGFR and stabilize EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR is relied on dimeric PKM2, and the protein half-life of mutant EGFR was decreased when PKM2 was forced to form tetramer after treating activators. Clinical levels of PKM2 positively correlate with mutant EGFR expression and correlate with patient outcome.Most of solid tumors suffer from glucose limited since the less amounts of vessels into tumor core. In the second part of the study, we found the nuclear translocation of the glycolic key enzyme, PKM2, in response to glucose deprivation in cancer cells. We demonstrate that glucose deprivation stimulates the AMPK activation and results in the nuclear translocation of PKM2 through Ran protein. Nuclear PKM2 then binds with OCT4 to promote the expression of cancer stemness-related genes. Thus, the nuclear PKM2 is able to enrich the cancer stem cell population. Furthermore, the nuclear PKM2 promotes cancer metastasis in an orthotopic xenograft model. Our findings provide first evidence that the cytosolic nutrient sensor AMPK works as a cooperator to help PKM2 carry out its nonmetabolic function in nucleus, and that is necessary for repopulation of cancer cells against and adapt to the metabolic stress.These results reveal a previously undescribed non-glycolysis function of PKM2 in cytoplasm and nucleus, and that provide a novel insight for the scientists to develop the drugs which target on PKM2.
KW - 表皮細胞生長因子受器
KW - 丙酮酸激酶M2
KW - 表皮細胞生長因子受器酪胺酸激酶的抑制劑
KW - 癌幹細胞
KW - 腺苷單磷酸活化蛋白激酶
KW - 葡萄糖缺乏
KW - EGFR
KW - PKM2
KW - EGFR TKIs,glucose deprivation
KW - cancer stem cell
KW - AMPK
UR - http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20948
U2 - 10.6342/NTU201700692
DO - 10.6342/NTU201700692
M3 - Doctoral Thesis
ER -
