Progesterone and its synthetic analogues act on cells through different types of receptors, affecting proliferation and apoptosis. These compounds exert their effect through the
nuclear receptors and the insufficiently studied membrane
progesterone receptors (mPRs) belonging to the
progestin and
adiponectin Q receptor (PAQR) family. We have identified two selective
ligands of mPRs that activate only this type of
progesterone receptors - 19-hydroxypregn-4-en-20-one (LS-01) and 19-hydroxy-5β-pregn-3-en-20-one (LS-02). The goal of this work is to study the effect of these compounds on proliferation and death of human pancreatic
adenocarcinoma cells BxPC3 and involvement of the two
kinases (
p38 MAPK and JNK) in signaling pathways activated by
progestins through mPRs. It was shown that
progesterone and the compound LS-01 significantly (p < 0.05) inhibited the BxPC3 cell viability, with JNK serving as a mediator. The identified targets of these two
steroids are the genes of the
proteins Ki67,
cyclin D1,
PCNA, and p21.
Progesterone and the compound LS-01 significantly (p < 0.05) stimulate DNA fragmentation, enhancing the cell death. The
p38 mitogen-activated protein kinase (MAPK) is a key mediator of this process. The BCL2A1
protein gene was identified as a target of both
steroids. The compound LS-02 significantly (p < 0.05) alters membrane permeability and changes the exposure of
phosphatidylserine on the outer membrane leaflet, also enhancing the cell death. This compound acts on these processes by activating both
kinases, JNK and
p38 MAPK. The compound LS-02 targets the genes encoding the
proteins HRK,
caspase 9, and DAPK.