Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells

Caroline H. Diep, Nathan J. Charles, C. Blake Gilks, Steve E. Kalloger, Peter A. Argenta, Carol A. Lange

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Loss of nuclear progesterone receptors (PR) and low circulating progesterone levels are associated with increased ovarian cancer (OC) risk. However, PR are abundantly expressed in a significant percentage of serous and endometrioid ovarian tumors; patients with PR+ tumors typically experience longer progression-free survival relative to those with PR-null tumors. The molecular mechanisms of these protective effects are poorly understood. To study PR action in OC in the absence of added estrogen (i.e., needed to induce robust PR expression), we created ES-2 OC cells stably expressing vector control or GFP-tagged PR-B (GFP-PR). Progestin (R5020) stimulation of ES-2 cells stably expressing GFP-PR induced cellular senescence characterized by altered cellular morphology, prolonged survival, senescence-associated β-galactosidase activity, G1 cell cycle arrest and upregulation of the cell cycle inhibitor, p21, as well as the Forkhead-box transcription factor, FOXO1; these results repeated in unmodified ER+/PR+ PEO 4 OC cells. PR-B and FOXO1 were detected within the same PRE-containing regions of the p21 upstream promoter. Knockdown of p21 resulted in molecular compensation via FOXO1-dependent upregulation of numerous FOXO1 target genes (p15, p16, p27) and an increased rate of senescence. Inhibition of FOXO1 (with AS1842856) or stable FOXO1 knockdown inhibited progestin-induced p21 expression and blocked progestin-induced senescence. Overall, these findings support a role for PR as a tumor suppressor in OC cells, which exhibits inhibitory effects by inducing FOXO1-dependent cellular senescence. Clinical "priming" of the PRFOXO1-p21 signaling pathway using PR agonists may provide a useful strategy to induce irreversible cell cycle arrest and thereby sensitize OC cells to existing chemotherapies as part of combination "two-step" therapies.

Original languageEnglish (US)
Pages (from-to)1433-1449
Number of pages17
JournalCell Cycle
Volume12
Issue number9
DOIs
StatePublished - May 1 2013

Fingerprint

Progesterone Receptors
Ovarian Neoplasms
Progestins
Cell Aging
Neoplasms
Up-Regulation
Promegestone
Galactosidases
p16 Genes
Forkhead Transcription Factors
G1 Phase Cell Cycle Checkpoints
Cytoplasmic and Nuclear Receptors
Cell Cycle Checkpoints
Disease-Free Survival
Progesterone
Cell Cycle
Estrogens
Drug Therapy
Survival

Keywords

  • AS1842856
  • Breast cancer
  • FOXO1
  • Forkhead transcription factor
  • Ovarian cancer
  • P21
  • Progesterone receptor
  • Progestin
  • Senescence

Cite this

Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells. / Diep, Caroline H.; Charles, Nathan J.; Gilks, C. Blake; Kalloger, Steve E.; Argenta, Peter A.; Lange, Carol A.

In: Cell Cycle, Vol. 12, No. 9, 01.05.2013, p. 1433-1449.

Research output: Contribution to journalArticle

Diep, Caroline H. ; Charles, Nathan J. ; Gilks, C. Blake ; Kalloger, Steve E. ; Argenta, Peter A. ; Lange, Carol A. / Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells. In: Cell Cycle. 2013 ; Vol. 12, No. 9. pp. 1433-1449.
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AU - Diep, Caroline H.

AU - Charles, Nathan J.

AU - Gilks, C. Blake

AU - Kalloger, Steve E.

AU - Argenta, Peter A.

AU - Lange, Carol A.

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AB - Loss of nuclear progesterone receptors (PR) and low circulating progesterone levels are associated with increased ovarian cancer (OC) risk. However, PR are abundantly expressed in a significant percentage of serous and endometrioid ovarian tumors; patients with PR+ tumors typically experience longer progression-free survival relative to those with PR-null tumors. The molecular mechanisms of these protective effects are poorly understood. To study PR action in OC in the absence of added estrogen (i.e., needed to induce robust PR expression), we created ES-2 OC cells stably expressing vector control or GFP-tagged PR-B (GFP-PR). Progestin (R5020) stimulation of ES-2 cells stably expressing GFP-PR induced cellular senescence characterized by altered cellular morphology, prolonged survival, senescence-associated β-galactosidase activity, G1 cell cycle arrest and upregulation of the cell cycle inhibitor, p21, as well as the Forkhead-box transcription factor, FOXO1; these results repeated in unmodified ER+/PR+ PEO 4 OC cells. PR-B and FOXO1 were detected within the same PRE-containing regions of the p21 upstream promoter. Knockdown of p21 resulted in molecular compensation via FOXO1-dependent upregulation of numerous FOXO1 target genes (p15, p16, p27) and an increased rate of senescence. Inhibition of FOXO1 (with AS1842856) or stable FOXO1 knockdown inhibited progestin-induced p21 expression and blocked progestin-induced senescence. Overall, these findings support a role for PR as a tumor suppressor in OC cells, which exhibits inhibitory effects by inducing FOXO1-dependent cellular senescence. Clinical "priming" of the PRFOXO1-p21 signaling pathway using PR agonists may provide a useful strategy to induce irreversible cell cycle arrest and thereby sensitize OC cells to existing chemotherapies as part of combination "two-step" therapies.

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