A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane

Font Mateu, Jofre, 1977-; Sanllehí, Pol; Sot, Jesús; Abad, Beatriz; Mateos, Nicolas; Torreno-Pina, Juan A.; Ferrari, Roberto; Wright, Roni H.G.; Garcia-Parajo, Maria F.; Joglar Tamargo, Jesús; Goñi, Félix M.; Beato, Miguel

doi:http://dx.doi.org/10.1007/s00018-024-05116-3

A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane

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Font-Mateu J, Sanllehí P, Sot J, Abad B, Mateos N, Torreno-Pina JA, et al. A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane. Cell Mol Life Sci. 2024 Feb 22;81(1):98. DOI: 10.1007/s00018-024-05116-3

Abstract

In hormone-responsive breast cancer cells, progesterone (P4) has been shown to act via its nuclear receptor (nPR), a ligand-activated transcription factor. A small fraction of progesterone receptor is palmitoylated and anchored to the cell membrane (mbPR) forming a complex with estrogen receptor alpha (ERα). Upon hormone exposure, either directly or via interaction with ERα, mbPR activates the SRC/RAS/ERK kinase pathway leading to phosphorylation of nPR by ERK. Kinase activation is essential for P4 gene regulation, as the ERK and MSK1 kinases are recruited by the nPR to its genomic binding sites and trigger chromatin remodeling. An interesting open question is whether activation of mbPR can result in gene regulation in the absence of ligand binding to intracellular progesterone receptor (iPR). This matter has been investigated in the past using P4 attached to serum albumin, but the attachment is leaky and albumin can be endocytosed and degraded, liberating P4. Here, we propose a more stringent approach to address this issue by ensuring attachment of P4 to the cell membrane via covalent binding to a stable phospholipid. This strategy identifies the actions of P4 independent from hormone binding to iPR. We found that a membrane-attached progestin can activate mbPR, the ERK signaling pathway leading to iPR phosphorylation, initial gene regulation and entry into the cell cycle, in the absence of detectable intracellular progestin.