PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Background: Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. Multiple different functions and cellular locations have been attributed to PGRMC1 in a variety of contexts, however the mechanisms underlying PGRMC1 biology remain obscure. The protein contains several phosphorylated residues including tyrosines which were acquired in animal evolution prior to bilateral symmetry, and could be involved with animal cell differentiation mechanisms. Results: Here we demonstrate that mutagenic manipulation of PGRMC1 phosphorylation status in MIA PaCa-2 pancreatic cells exerts broad pleiotropic effects, influencing cell plasticity and tumorigenicity, as assayed by cell biological and proteomics measurements. Relative to parental cells over-expressing hemagglutinin-tagged wild-type PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with Rho-kinase inhibitor-sensitive changes including altered cell shape, motility, increased PI3K/Akt activity, and fragmented mitochondrial morphology. An S57A/Y180F/S181A triple mutant reduced PI3K/Akt activity, indicating involvement of Y180 in PI3K/Akt induction. Both triple mutant and Y180F single mutant cells exhibited attenuated mouse xenograft tumor growth. Conclusions: Phosphorylation status of the PGRMC1 tyrosine 180 regulatory motif exerts dramatic influence over cancer cell biology, including Warburg effect-like glucose metabolism. In accompanying papers we show that: 1) the cells examined here exhibit dramatically altered metabolism and epigenetic status, with the triple mutant inducing hypermethylation similar to that of embryonic stem cells, and that 2) Y180 was acquired in evolution concurrently with appearance of the organizer that induces animal gastrulation. Taken together, these results indicate that the undescribed mechanisms regulating PGRMC1 phosphorylation may be of great disease relevance and merit urgent investigation.