Abstract
BackgroundProgesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms.ResultsWe demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) 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 increased PI3K/AKT activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/AKT activation. Mutation of Y180F strongly attenuated subcutaneous xenograft tumor growth in NOD-SCID gamma mice. Elsewhere we demonstrate altered metabolism, mutation incidence, and epigenetic status in these cells.ConclusionsAltogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.
Highlights
Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes
We focus our analysis onto comparisons between WT, double mutant (DM) and triple mutant (TM) cells
DM and TM cells exhibited primarily rounded morphology (Fig. 1e), which was reminiscent of the reported mesenchymal-amoeboid transition (MAT) of MIA PaCa-2 (MP) cells [35]
Summary
Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. Its subcellular localization can be cytoplasmic, nuclear/nucleolar, mitochondrial, endoplasmic reticulum, cytoplasmic vesicles, or extracellular [1,2,3] It is involved in cell cycle processes at the G1 checkpoint and during mitosis [4,5,6,7,8,9], and elevated PGRMC1 expression has been associated with poor prognosis in multiple types of cancer [2, 10,11,12,13,14,15]. These and Y180 can all be phosphorylated in vivo, and constitute a potential regulated signaling module [19]
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