The B55α Subunit of PP2A Drives a p53-Dependent Metabolic Adaptation to Glutamine Deprivation

Abstract

Glutamine is an essential nutrient for cancer cell survival and proliferation, yet the signaling pathways that sense glutamine levels remain uncharacterized. Here, we report that the 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. This study delineates a previously unidentified signaling pathway that senses glutamine levels as well as provides important evidence that protein phosphatase complexes are actively involved in signal transduction.

Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway

“…Loss of Ras protein expression causes widespread transcriptional activation of p53, similar to that observed in other experimental settings, such as low glucose or low serum (22,23). Therefore, it seems plausible that lack of mitogenic signaling, as previously observed under different nutritional deprivation conditions, causes p53 activation, leading to reversible cell cycle arrest through increased transcription of p21Cip1 (24)(25)(26).…”

Autophagy in cellular metabolism and cancer

“…During the progression of solid tumors, an increase in tumor size produces stress on cells within central regions, as these areas become hypoxic and nutrient deficient due to inadequate blood supply (94). Even as angiogenesis occurs, regions within solid tumors may still experience metabolic stress as a result of low glucose and glutamine availability (95)(96)(97), due to the leakiness of tumor-associated vessels as well as continued hypovascularization (98). Under such conditions, tumor cells can use autophagy to provide an alternative energy source for survival and proliferation (99,100).…”

Inhibition of Protein Phosphatase 2A Enhances Cytotoxicity and Accessibility of Chemotherapeutic Drugs to Hepatocellular Carcinomas

“…Because of the complicated constitutive and various signaling pathways involving PP2A, this ubiquitous phosphatase may play distinct roles in different tissue and disease states. For instance, the B55a regulatory subunit of PP2A was shown to enhance the survival of human fibrosarcoma cells during glutamine deprivation (7), whereas inhibition of the B56g subunit induces tumorigenic transformation of human embryonic kidney cells (8), thereby acting like B56a as a tumor suppressor (9). This diversity of PP2A function in tumorigenesis suggests that in certain circumstances targeting PP2A may be an effective cancer strategy.…”