Аннотация:Progesterone (P4) plays an important role in regulation of reproductive function and acts through classical nuclear receptors (nPRs) and membrane receptors (mPRs). Controversial effects of P4 on differentiation, proliferation and cell death in different tissues were described. For example, P4 shows carcinogenic activity in breast cancer, but we found its anti-proliferative effects in BxPC3 (pancreatic adenocarcinoma) cells. According to RT-PCR data these cells have high level of mPRs mRNA and lack of nPRs mRNA. Two selective ligands of mPRs – 19-hydroxypregn-4en-20-one (I) and 19- hydroxy-5β-pregn-3-en-20-one (II) were identified previously.
In this study we have tested the action of selective ligands of mPRs and P4 on the proliferation of BxPC3 cell line in the presence or absence of two inhibitors of different MAPK (p38 and JNK) using XTT test (cell viability test).
In the absence of MAPK inhibitors viability of BxPC3 cells decreased at the 5 µM, 20 µM P4 and 20 µM (I). The p38 inhibitor showed the same effect on cell viability at 1 µM P4, 1 µM (I) and 20 µM (II).
In the presence of JNK inhibitor viability of BxPC3 cells decreased only when 20 µM P4 was used. These data suggested that (I) exerts anti-proliferative effect on BxPC3 cells by acting through mPRs especially in the presence of p38 inhibitor. In the presence of JNK inhibitor, (I) did not affect viability of BxPC3 cells
Thereby JNK seems to play a key role in the mPRs signaling pathway. The mPRs selective ligands can be used instead of P4 to prevent its side effects in tissues with classical receptors.
This work was supported by the Russian Foundation for Basic Research (project 17-04-00234).