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

Samaneh Yazdani, Atsuko Kasajima, Yoshiaki Onodera, Keely May McNamara, Kazue Ise, Yasuhiro Nakamura, Tomoyoshi Tachibana, Fuyuhiko Motoi, Michiaki Unno, Hironobu Sasano

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)243-253
Number of pages11
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume178
DOIs
Publication statusPublished - 2018 Apr

Keywords

  • Cell cycle
  • Cyclin
  • Cyclin dependent kinase
  • Neuroendocrine neoplasm
  • PCR array
  • Progesterone receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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