Prevention of epithelial to mesenchymal transition in colorectal carcinoma by regulation of the E-cadherin-β-catenin-vinculin axis

Pal, Ipsita; Rajesh, Y.; Banik, Payel; Dey, Goutam; Dey, Kaushik; Bharti, Rashmi; Naskar, Deboki; Chakraborty, Sanjoy; Ghosh, Sudip Kumar; Das, Swadesh K.; Emdad, Luni; Kundu, Subhas C.; Fisher, Paul B.; Mandal, Mahitosh

doi:10.1016/j.canlet.2019.03.008

“…Similarly to our results, those authors concluded that "that PGRMC1 is able to suppress broad networks necessary for multi-lineage fate specification." Our hypothesis suggests that PGRMC1 Y180 phosphorylation and PI3K/Akt activity could be associated with elevated GSK-3β Ser9 phosphorylation and β-catenin signaling in some cancers (Pal et al, 2019).…”

Section: Discussionmentioning

confidence: 81%

“…Proteins of the actin cytoskeleton were more abundant in DM cells ( Figure S4A), one of which was vinculin ( Figure S1B), an actin filament-binding protein associated with cell differentiation status, locomotion, and PI3K/Akt, E-cadherin, and β-catenin-regulated Wnt signaling in colon carcinoma (Le Clainche et al, 2010;Pal et al, 2019). We attenuated vinculin levels in MP, WT, and DM cells via shRNA.…”

Section: Enhanced Dm Cell Motility Requires Vinculinmentioning

confidence: 94%

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

Thejer

¹

,

Adhikary

²

,

Kaur

³

et al. 2019

Preprint

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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. Here, 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 mouse xenograft tumor growth. An accompanying paper demonstrates altered metabolism, mutation incidence, and epigenetic status in these cells, indicating that PGRMC1 phosphorylation strongly influences cancer biology.

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“…Similarly to our results, those authors concluded that "that PGRMC1 is able to suppress broad networks necessary for multi-lineage fate specification." Our hypothesis suggests that PGRMC1 Y180 phosphorylation and PI3K/Akt activity could be associated with elevated GSK-3β Ser9 phosphorylation and β-catenin signaling in some cancers [57].…”

Section: Discussionmentioning

confidence: 81%

“…S4A), one of which was vinculin ( Fig. S1B), an actin filament-binding protein associated with cell differentiation status, locomotion, and PI3K/Akt, E-cadherin, and β-catenin-regulated Wnt signaling in colon carcinoma [56,57]. We attenuated vinculin levels in MP, WT, and DM cells via shRNA.…”

Section: Vinculin Elevated In Dm Is Required For Cell Motilitymentioning

confidence: 93%

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

Thejer

¹

,

Adhikary

²

,

Kaur

³

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

“…Similarly to our results, those authors concluded that "that PGRMC1 is able to suppress broad networks necessary for multi-lineage fate specification." Our hypothesis suggests that PGRMC1 Y180 phosphorylation and PI3K/Akt activity could be associated with elevated GSK-3β Ser9 phosphorylation and β-catenin signaling in some cancers [47].…”

Section: Tcp1 (P17987mentioning

confidence: 81%

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

Thejer

¹

,

Adhikary

²

,

Kaur

³

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Prevention of epithelial to mesenchymal transition in colorectal carcinoma by regulation of the E-cadherin-β-catenin-vinculin axis

Cited by 30 publications

References 51 publications

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

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

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

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

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