PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth

Abstract

Background Progesterone 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. Results We 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. Conclusions Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.

PGRMC Proteins Are Coming of Age: A Special Issue on the Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology

“…Altered mitochondrial biology was also associated with PGRMC1-driven changes in glycolysis [ 63 ], concordant with our earlier hypothesis that PGRMC1 could be associated with the Warburg effect. In 2019, Sabbir independently demonstrated that HEK293 cells induced aerobic glycolysis upon P4 treatment, which involved altered abundance of post-translationally modified PGRMC1 isoforms.…”

“…Somehow, this seemed to be related to mitochondrial function [ 56 ], and we showed that PGRMC1 phosphorylation status can exert the most dramatic effects on mitochondrial form (fission versus fusion) and cell metabolism. This involved not just mitochondria, but also the PI3K/Akt pathway via tyrosine 180 [ 63 ]. PGRMC1 modulation of the Akt pathway has been reported multiple times [ 4 , 64 , 65 ].…”

Identification of the Biomarkers and Pathological Process of Heterotopic Ossification: Weighted Gene Co-Expression Network Analysis

“…It is worth noting that in this study, 8 (ACTR3, ARF4, PGRMC1, RPS23, WDR12, ACTR2, SIAH1, and RPS27L) of 12 hub genes are related to cancers, such as lung cancer, epithelial ovarian cancer, gastric cancer, glioblastoma, breast cancer, and esophageal cancer (51,54,(57)(58)(59)(60)(61)(62)(63). A last year's research showed pulmonary adenocarcinoma cells around the ossification expressed bone morphogenetic protein-2 and osteopontin, which generally induce and stimulate bone formation (64,65).…”

Absence of progesterone receptor membrane component 1 reduces migration and metastasis of breast cancer

“…First, we observed that genetic deletion or silencing of Pgrmc1 resulted in decreased expression of FAK, which was shown to negatively regulate invadopodia and positively regulate the invasion of breast cancer cells [ 27 ]. A recent study showed that the PGRMC1 protein is post-translationally modified or phosphorylated by progesterone [ 28 ], and that its phosphorylation influences the activation of FAK and alters the cellular migration depending on the phosphorylation site [ 29 ]. Also, similar to a previous study that demonstrated the lack of lung metastasis in FAK-deficient PyMT mice [ 30 ], the FAK expression was suppressed in Pgrmc1 KO mice in this study.…”