| Summary: | 碩士 === 國立臺灣大學 === 生化科學研究所 === 103 === The reprogramming of cancer metabolism is recognized as the Warburg effect, which demonstrates that cancer cells rely on aerobic glycolysis for energy generation. However, cancer cells are generally glucose deprived due to rapid proliferation and poor vascularization, hence cancer cells are forced to cope with glucose depletion stress and survive. Previous studies revealed that cancer cells manipulate the Warburg effect, gluconeogenesis pathway, migration ability, ER stress and cancer stem cell phenotypes in response to glucose depletion. Focus on the correlation between cancer stem cells and glucose depletion, it has been reported that the brain tumor initiation cell (BTIC) phenotypes are enhanced during glucose depletion, and BTICs preferentially survive under glucose depletion through enhancing glucose uptake. Nevertheless, some reports have opposite suggestions that glucose starvation causes a rapid depletion of side population (SP) cells, which are stem-like cells within cancer cells. Hence, the role of glucose depletion in affecting cancer stem cells largely remains unclear. Herein, we observed that glucose depletion enhanced the sphere formation ability and up-regulated the expression of cancer stem cell markers like CD133, CD44, EPCAM, NANOG, NOTCH1, OCT4 and SOX2. We confirmed that PKM2 (pyruvate kinase M2), the glycolytic key enzyme, plays an important role in this response. By knockdown PKM2, cancer stemness gene expression and sphere formation ability which were enhanced by glucose depletion were abolished. Recent evidences reveal that PKM2 not only plays a role in glycolysis, but also acts as a protein kinase or transcriptional coactivator in the nucleus. Thus we analyzed the distribution of PKM2 during glucose depletion. By immunofluorescence staining and cell fractionation, we confirmed that glucose depletion induced PKM2 nuclear translocation. Besides, AMPK is a key regulator of energy homeostasis. We dissect that AMPK, which is activated by glucose depletion, interacted with PKM2 and regulated its Tyr105 phosphorylation, resulting in the nuclear translocation of PKM2. In fact, we observed that only a small fraction of cancer cells was nuclear PKM2 accumulated. Thus we proposed that glucose depletion induced PKM2 nuclear translocation and cancer stem cell properties in a small population of cancer cells, which could preferentially survive and lead to cancer repopulation. We certainly found that the sorted CD133 positive subpopulations within cancer cells were nuclear PKM2 enriched, whereas CD133 negative cells were not. Collectively, we demonstrated a new role of nuclear PKM2 on glucose depletion-induced cancer stem cell properties and cancer repopulation, which helps cancer cells to thrive against this metabolic stress.
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