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Cytotoxic Effects of the Selective Ligands of Membrane Progesterone Receptors in Human Pancreatic Adenocarcinoma Cells BxPC3

Alexey I. Goncharov1, Inna S. Levina2, Viktoriia L. Shliapina1, Ivan A. Morozov3, Petr M. Rubtsov3, Igor V. Zavarzin2, Olga V. Smirnova1, and Tatiana A. Shchelkunova1,a*

1Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

2Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia

3Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

* To whom correspondence should be addressed.

Received August 31, 2021; Revised September 23, 2021; Accepted September 23, 2021
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.
KEY WORDS: progesterone, selective ligands, proliferation, apoptosis, expression, nuclear receptor, membrane progesterone receptors

DOI: 10.1134/S0006297921110080