Progesterone arrested cell cycle progression through progesterone receptor isoform A in pancreatic neuroendocrine neoplasm.

Abstract

In pancreatic neuroendocrine neoplasms (Pan-NEN) progesterone signaling has been shown to have both inhibitory and stimulatory effects on cell proliferation. The ability of progesterone to inhibit tumor proliferation is of particular interest and is suggested to be mediated through the less abundantly expressed progesterone receptor (PR) isoform A (PRA). To date the mechanistic processes underlying this inhibition of proliferation remain unclear. To examine the mechanism of PRA actions, the human Pan-NEN cell line QGP-1, that endogenously expresses PR isoform B (PRB) without PRA, was transfected with PRA. PRA transfection suppressed the majority of cell cycle related genes increased by progesterone including cyclin A2 (CCNA2), cyclin B1 (CCNB1), cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 2 (CDK2). Importantly, following progesterone administration cell cycle distribution was shifted to S and G2/M phases in the naïve cell line but in PRA-transfected cells, this effect was suppressed. To see if these mechanistic insights were confirmed in patient samples PRA, PRB, CCNA2, CCNB, CDK1 and CDK2 immunoreactivities were assessed in Pan-NEN cases. Higher levels of cell cycle markers were associated with higher WHO grade tumors and correlations between the markers suggested formation of cyclin/CDK activated complexes in S and G2/M phases. PRA expression was associated with inverse correlation of all cell cycle markers. Collectively, these results indicate that progesterone signals through PRA negatively regulates cell cycle progression through suppressing S and G2/M phases and downregulation of cell cycle phases specific cyclins/CDKs.

• Authors: Samaneh Yazdani, Atsuko Kasajima, Yoshiaki Onodera, Keely May McNamara, Kazue Ise, Yasuhiro Nakamura, Tomoyoshi Tachibana, Fuyuhiko Motoi, Michiaki Unno, Hironobu Sasano
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 178 Pg. 243-253 (04 2018) ISSN: 1879-1220 [Electronic] England
• PMID: 29331723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Protein Isoforms
• Receptors, Progesterone
• progesterone receptor A
• Progesterone

Topics

• Cell Cycle (drug effects)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Neuroendocrine Tumors (drug therapy, metabolism, pathology)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation
• Progesterone (pharmacology)
• Protein Isoforms
• Receptors, Progesterone (genetics, metabolism)
• Tumor Cells, Cultured