Wang W.,515 Holcombe Boulevard |
Xiao Z.-D.,515 Holcombe Boulevard |
Li X.,515 Holcombe Boulevard |
Aziz K.E.,515 Holcombe Boulevard |
And 4 more authors.
Nature Cell Biology | Year: 2015
The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention. © 2015 Macmillan Publishers Limited.
Younes A.,515 Holcombe Boulevard |
Samad N.,515 Holcombe Boulevard
Oncologist | Year: 2011
The mammalian target of rapamycin (mTOR) is an in-tracellular serine/threonine kinase that exists as a downstream component of numerous signaling pathways. The activation of mTOR results in the production of proteins involved in cell metabolism, growth, proliferation, and angiogenesis. Aberrant activation of mTOR signaling has been identified in a number of cancers, and targeted inhibition of mTOR has been successful in achieving tumor responses, prolonging progression-free survival, and increasing overall survival in various oncologic patient populations. In particular, persistent activation of mTOR signaling has been identified in cell lines and patient samples with leukemias, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and Waldenström's macroglobulinemia (WM). In vitro and preclinical studies using agents that inhibit mTOR signaling have demonstrated cytostatic and cytotoxic effects in these hematologic malignancies, suggesting that mTOR is a rational target for therapy in these disease states. In addition, the combination of mTOR inhibitors with traditional therapies may help to overcome the development of resistance and may improve response rates over those seen with established regimens through synergistic or additive effects. Inhibitors of mTOR signaling currently are being investigated in clinical trials of hematologic malignancies as single agents and as components of combination regimens. Thus far, promising results have been seen with the application of mTOR inhibitors as single agents in patients with relapsed or refractory leukemia, HL, NHL, MM, and WM. © AlphaMed Press.