Induction of senescence by progesterone receptor-B activation in response to cAMP in ovarian cancer cells

Akira Takahashi, Kiyoko Kato, Ayumi Kuboyama, Takafumi Inoue, Yoshihiro Tanaka, Aya Kuhara, Katsuyuki Kinoshita, Satoru Takeda, Norio Wake

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Abstract

Objective: Progesterone receptor (PR) expression is a favorable prognostic marker in ovarian cancer. We previously demonstrated that the induction of PR-B by treatment with cAMP was associated with G0/G1 arrest of the cell cycle and growth inhibition in NIH 3T3 cells. In this study, we examined the effect of cAMP treatment on cell growth in Ras-transformed NIH3T3 cells and ovarian cancer cells. Methods: 1) The levels of PR-B and cell cycle associated proteins (p21, p27 and Rb) following treatment with cAMP in the Ras-transformed NIH3T3 cells (K12V) and ovarian cancer cell lines (SKOV cells) were investigated by Western blots. 2) The effects of PR overexpression following treatment with cAMP or after infection of an adenovirus expressing PR-B on cell growth and tumorigenicity in a soft agar culture were examined. Results: 1) Treatment with cAMP increased PR-B and p27 levels in K12V cells and inhibited cell growth by inducing premature senescence. Induction of senescence was specific to the transformed cells. 2) In SKOV cells, treatment with cAMP induced PR-B, p27 and p21 expression, reduced the level of phosphorylated Rb, caused accumulation of cells in the G0/G1 fraction of the cell cycle, and induced senescence. 3) Both anchorage-dependent and -independent SKOV cell growths were inhibited by cAMP treatment. 4) Induction of both the expression and transcriptional activity of PR-B is critical for the induction of senescence and suppression of tumorigenicity. Conclusion: Treatment of cAMP, through activation of PR-B, induced senescence and suppressed tumorigenicity in ovarian cancer cells.

Original languageEnglish
Pages (from-to)270-276
Number of pages7
JournalGynecologic Oncology
Volume113
Issue number2
DOIs
Publication statusPublished - May 1 2009

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Ovarian Neoplasms
Growth
Progesterone Receptors
progesterone receptor B
G1 Phase Cell Cycle Checkpoints
Adenoviridae Infections
NIH 3T3 Cells
Cell Cycle Proteins
Agar
Cell Cycle
B-Lymphocytes
Western Blotting
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Obstetrics and Gynaecology

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Induction of senescence by progesterone receptor-B activation in response to cAMP in ovarian cancer cells. / Takahashi, Akira; Kato, Kiyoko; Kuboyama, Ayumi; Inoue, Takafumi; Tanaka, Yoshihiro; Kuhara, Aya; Kinoshita, Katsuyuki; Takeda, Satoru; Wake, Norio.

In: Gynecologic Oncology, Vol. 113, No. 2, 01.05.2009, p. 270-276.

Research output: Contribution to journalArticle

Takahashi, A, Kato, K, Kuboyama, A, Inoue, T, Tanaka, Y, Kuhara, A, Kinoshita, K, Takeda, S & Wake, N 2009, 'Induction of senescence by progesterone receptor-B activation in response to cAMP in ovarian cancer cells', Gynecologic Oncology, vol. 113, no. 2, pp. 270-276. https://doi.org/10.1016/j.ygyno.2008.12.032
Takahashi, Akira ; Kato, Kiyoko ; Kuboyama, Ayumi ; Inoue, Takafumi ; Tanaka, Yoshihiro ; Kuhara, Aya ; Kinoshita, Katsuyuki ; Takeda, Satoru ; Wake, Norio. / Induction of senescence by progesterone receptor-B activation in response to cAMP in ovarian cancer cells. In: Gynecologic Oncology. 2009 ; Vol. 113, No. 2. pp. 270-276.
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AU - Takahashi, Akira

AU - Kato, Kiyoko

AU - Kuboyama, Ayumi

AU - Inoue, Takafumi

AU - Tanaka, Yoshihiro

AU - Kuhara, Aya

AU - Kinoshita, Katsuyuki

AU - Takeda, Satoru

AU - Wake, Norio

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N2 - Objective: Progesterone receptor (PR) expression is a favorable prognostic marker in ovarian cancer. We previously demonstrated that the induction of PR-B by treatment with cAMP was associated with G0/G1 arrest of the cell cycle and growth inhibition in NIH 3T3 cells. In this study, we examined the effect of cAMP treatment on cell growth in Ras-transformed NIH3T3 cells and ovarian cancer cells. Methods: 1) The levels of PR-B and cell cycle associated proteins (p21, p27 and Rb) following treatment with cAMP in the Ras-transformed NIH3T3 cells (K12V) and ovarian cancer cell lines (SKOV cells) were investigated by Western blots. 2) The effects of PR overexpression following treatment with cAMP or after infection of an adenovirus expressing PR-B on cell growth and tumorigenicity in a soft agar culture were examined. Results: 1) Treatment with cAMP increased PR-B and p27 levels in K12V cells and inhibited cell growth by inducing premature senescence. Induction of senescence was specific to the transformed cells. 2) In SKOV cells, treatment with cAMP induced PR-B, p27 and p21 expression, reduced the level of phosphorylated Rb, caused accumulation of cells in the G0/G1 fraction of the cell cycle, and induced senescence. 3) Both anchorage-dependent and -independent SKOV cell growths were inhibited by cAMP treatment. 4) Induction of both the expression and transcriptional activity of PR-B is critical for the induction of senescence and suppression of tumorigenicity. Conclusion: Treatment of cAMP, through activation of PR-B, induced senescence and suppressed tumorigenicity in ovarian cancer cells.

AB - Objective: Progesterone receptor (PR) expression is a favorable prognostic marker in ovarian cancer. We previously demonstrated that the induction of PR-B by treatment with cAMP was associated with G0/G1 arrest of the cell cycle and growth inhibition in NIH 3T3 cells. In this study, we examined the effect of cAMP treatment on cell growth in Ras-transformed NIH3T3 cells and ovarian cancer cells. Methods: 1) The levels of PR-B and cell cycle associated proteins (p21, p27 and Rb) following treatment with cAMP in the Ras-transformed NIH3T3 cells (K12V) and ovarian cancer cell lines (SKOV cells) were investigated by Western blots. 2) The effects of PR overexpression following treatment with cAMP or after infection of an adenovirus expressing PR-B on cell growth and tumorigenicity in a soft agar culture were examined. Results: 1) Treatment with cAMP increased PR-B and p27 levels in K12V cells and inhibited cell growth by inducing premature senescence. Induction of senescence was specific to the transformed cells. 2) In SKOV cells, treatment with cAMP induced PR-B, p27 and p21 expression, reduced the level of phosphorylated Rb, caused accumulation of cells in the G0/G1 fraction of the cell cycle, and induced senescence. 3) Both anchorage-dependent and -independent SKOV cell growths were inhibited by cAMP treatment. 4) Induction of both the expression and transcriptional activity of PR-B is critical for the induction of senescence and suppression of tumorigenicity. Conclusion: Treatment of cAMP, through activation of PR-B, induced senescence and suppressed tumorigenicity in ovarian cancer cells.

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