Signal transduction and Cancer Metabolism
Tumor cells often display fundamental changes in metabolism and increase their uptake of nutrients to meet the increased bioenergetic demands of proliferation. Glucose and glutamine are two main nutrients whose uptake is directly controlled by signal transduction and are essential for tumor cell survival and proliferation. Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen.
In addition to glucose, glutamine is another essential nutrient whose uptake is directly controlled by oncogenes, and it is critical for cancer cell survival and proliferation. During tumor growth, increased uptake of nutrients and rapid accumulation of cells can outstrip the supply of essential nutrients, including glucose and glutamine. How tumor cells survive these temporary periods of nutrient deprivation is unclear, but is necessary for tumorigenesis to persist. The major goal of our laboratory is to delineate the strategies used by tumor cells to survive periods of nutrient deprivation and then to develop novel therapies targeting nutrient-sensing pathways of neoplastic cells. Exciting progress has been made over the past 20 years in elucidating how cancer cells survive glucose deprivation via mTOR, AMPK and p53 pathway.
In contrast, less is known about the signal transduction pathways that regulate tumor cells’ survival during glutamine deprivation, in spite of the evidence that has been noticed for many years, that glutamine fell from a high level in normal tissue to a level not detectable in different solid tumors. Thus, identifying the critical regulators that control tumor cell survival during glutamine deprivation may lead to the development of novel and safer cancer therapies. We recently discovered that protein phosphatase 2A (PP2A)-associated protein, α4, plays a conserved role in glutamine sensing. α4 promotes assembly of an adaptive PP2A complex containing the B55α regulatory subunit via providing the catalytic subunit upon glutamine deprivation. Moreover, B55α is specifically induced upon glutamine deprivation in a ROS-dependent manner to activate p53 and promote cell survival. B55α activates p53 through direct interaction and dephosphorylation of EDD, a negative regulator of p53. Importantly, the B55α-EDD-p53 pathway is essential for cancer cell survival and tumor growth under low glutamine conditions in vitro and in vivo. In future work, we will focus on understanding how p53 activation regulates tumor cell survival under glutamine deprivation, and identify critical p53 targets that contribute to cancer cell survival under glutamine limitation.
Our long-term goal is to identify the signals that allow communication between oncogenic pathways and tumor cell metabolism and develop novel therapeutics targeting metabolic differences between rapidly-proliferating cancer cells and normal cells.
Regulation of Protein Phosphatase 2A Complexes
Reversible protein phosphorylation is the major regulatory mechanism used by cells to respond to environmental and nutritional stresses. Aberrant regulation of this activity leads to dysregulated cellular behavior and disease phenotypes, including many forms of cancer. Although we know much about how protein kinases function in specific signaling governed by phosphorylation, whether protein phosphatases are also regulated and actively function in the process to counteract kinase function has not been established. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many signaling pathways. Unlike kinases, serine/threonine phosphatases are promiscuously active and their specificity is governed largely by associated proteins. Thus, the specificity of PP2A is conferred by assembly of a trimeric complex including a catalytic C subunit, a scaffolding A subunit, and one of the sixteen regulatory B subunits. In addition to interacting with conventional A and B subunits, the C subunit reportedly forms two other distinct complexes with proteins designated α4 (Tap42 in yeast) and Tiprl (Tip41 in yeast). Our laboratory also interested in characterizing molecular mechanisms underlying the response of PP2A complexes to stress signals.
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