Specific Chemopreventive Agents Trigger Proteasomal Degradation of G 1 Cyclins

Implications for Combination Therapy

Konstantin H. Dragnev, Ian Pitha-Rowe, Yan Ma, W. Jeffrey Petty, David Sekula, Bryan Murphy, Mara Rendi, Nanjoo Suh, Neil B. Desai, Michael B. Sporn, Sarah J. Freemantle, Ethan Dmitrovsky

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Purpose: There is a need to identify cancer chemoprevention mechanisms. We reported previously that all-transretinoic acid (RA) prevented carcinogenic transformation of BEAS-2B immortalized human bronchial epithelial cells by causing G1 arrest, permitting repair of genomic DNA damage. G 1 arrest was triggered by cyclin D1 proteolysis via ubiquitin-dependent degradation. This study investigated which chemopreventive agents activated this degradation program and whether cyclin E was also degraded. Experimental Design: This study examined whether: (a) cyclin E protein was affected by RA treatment; (b) cyclin degradation occurred in derived BEAS-2B-R1 cells that were partially resistant to RA; and (c) other candidate chemopreventive agents caused cyclin degradation. Results: RA treatment triggered degradation of cyclin E protein, and ALLN, a proteasomal inhibitor, inhibited this degradation. Induction of the retinoic acid receptor β, growth suppression, and cyclin degradation were each inhibited in BEAS-2B-R1 cells. Transfection experiments in BEAS-2B cells indicated that RA treatment repressed expression of wild-type cyclin Dl and cyclin E, but ALLN inhibited this degradation. Mutation of threonine 286 stabilized transfected cyclin D1, and mutations of threonines 62 and 380 stabilized transfected cyclin E, despite RA treatment. Specific chemopreventive agents triggered cyclin degradation. Nonclassical retinoids (fenretinide and retinoid X receptor agonists) and a synthetic triterpenoid (2-cyano-3,12-dioxooleana-1, 9-dien-28-oic acid) each suppressed BEAS-2B growth and activated this degradation program. However, a vitamin D3 analog (RO-24-5531), a cyclooxygenase inhibitor (indomethacin), and a peroxisome proliferator-activated receptor γ agonist (rosiglitazone) each suppressed BEAS-2B growth, but did not cause cyclin degradation. BEAS-2B-R1 cells remained responsive to nonclassical retinoids and to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid. Conclusions: Specific chemopreventive agents activate cyclin proteolysis. Yet, broad resistance did not occur after acquired resistance to a single agent. This provides a therapeutic rationale for combination chemoprevention with agents activating non-cross-resistant pathways.

Original languageEnglish (US)
Pages (from-to)2570-2577
Number of pages8
JournalClinical Cancer Research
Volume10
Issue number7
DOIs
StatePublished - Apr 1 2004

Fingerprint

Cyclin G
Cyclins
Cyclin E
rosiglitazone
Cyclin D1
Retinoids
Chemoprevention
Threonine
Therapeutics
Proteolysis
Acids
Growth
Fenretinide
Retinoid X Receptors
Mutation
Retinoic Acid Receptors
Peroxisome Proliferator-Activated Receptors
Cyclooxygenase Inhibitors
Cholecalciferol
Ubiquitin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dragnev, K. H., Pitha-Rowe, I., Ma, Y., Petty, W. J., Sekula, D., Murphy, B., ... Dmitrovsky, E. (2004). Specific Chemopreventive Agents Trigger Proteasomal Degradation of G 1 Cyclins: Implications for Combination Therapy. Clinical Cancer Research, 10(7), 2570-2577. https://doi.org/10.1158/1078-0432.CCR-03-0271

Specific Chemopreventive Agents Trigger Proteasomal Degradation of G 1 Cyclins : Implications for Combination Therapy. / Dragnev, Konstantin H.; Pitha-Rowe, Ian; Ma, Yan; Petty, W. Jeffrey; Sekula, David; Murphy, Bryan; Rendi, Mara; Suh, Nanjoo; Desai, Neil B.; Sporn, Michael B.; Freemantle, Sarah J.; Dmitrovsky, Ethan.

In: Clinical Cancer Research, Vol. 10, No. 7, 01.04.2004, p. 2570-2577.

Research output: Contribution to journalArticle

Dragnev, KH, Pitha-Rowe, I, Ma, Y, Petty, WJ, Sekula, D, Murphy, B, Rendi, M, Suh, N, Desai, NB, Sporn, MB, Freemantle, SJ & Dmitrovsky, E 2004, 'Specific Chemopreventive Agents Trigger Proteasomal Degradation of G 1 Cyclins: Implications for Combination Therapy', Clinical Cancer Research, vol. 10, no. 7, pp. 2570-2577. https://doi.org/10.1158/1078-0432.CCR-03-0271
Dragnev, Konstantin H. ; Pitha-Rowe, Ian ; Ma, Yan ; Petty, W. Jeffrey ; Sekula, David ; Murphy, Bryan ; Rendi, Mara ; Suh, Nanjoo ; Desai, Neil B. ; Sporn, Michael B. ; Freemantle, Sarah J. ; Dmitrovsky, Ethan. / Specific Chemopreventive Agents Trigger Proteasomal Degradation of G 1 Cyclins : Implications for Combination Therapy. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 7. pp. 2570-2577.
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AU - Pitha-Rowe, Ian

AU - Ma, Yan

AU - Petty, W. Jeffrey

AU - Sekula, David

AU - Murphy, Bryan

AU - Rendi, Mara

AU - Suh, Nanjoo

AU - Desai, Neil B.

AU - Sporn, Michael B.

AU - Freemantle, Sarah J.

AU - Dmitrovsky, Ethan

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N2 - Purpose: There is a need to identify cancer chemoprevention mechanisms. We reported previously that all-transretinoic acid (RA) prevented carcinogenic transformation of BEAS-2B immortalized human bronchial epithelial cells by causing G1 arrest, permitting repair of genomic DNA damage. G 1 arrest was triggered by cyclin D1 proteolysis via ubiquitin-dependent degradation. This study investigated which chemopreventive agents activated this degradation program and whether cyclin E was also degraded. Experimental Design: This study examined whether: (a) cyclin E protein was affected by RA treatment; (b) cyclin degradation occurred in derived BEAS-2B-R1 cells that were partially resistant to RA; and (c) other candidate chemopreventive agents caused cyclin degradation. Results: RA treatment triggered degradation of cyclin E protein, and ALLN, a proteasomal inhibitor, inhibited this degradation. Induction of the retinoic acid receptor β, growth suppression, and cyclin degradation were each inhibited in BEAS-2B-R1 cells. Transfection experiments in BEAS-2B cells indicated that RA treatment repressed expression of wild-type cyclin Dl and cyclin E, but ALLN inhibited this degradation. Mutation of threonine 286 stabilized transfected cyclin D1, and mutations of threonines 62 and 380 stabilized transfected cyclin E, despite RA treatment. Specific chemopreventive agents triggered cyclin degradation. Nonclassical retinoids (fenretinide and retinoid X receptor agonists) and a synthetic triterpenoid (2-cyano-3,12-dioxooleana-1, 9-dien-28-oic acid) each suppressed BEAS-2B growth and activated this degradation program. However, a vitamin D3 analog (RO-24-5531), a cyclooxygenase inhibitor (indomethacin), and a peroxisome proliferator-activated receptor γ agonist (rosiglitazone) each suppressed BEAS-2B growth, but did not cause cyclin degradation. BEAS-2B-R1 cells remained responsive to nonclassical retinoids and to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid. Conclusions: Specific chemopreventive agents activate cyclin proteolysis. Yet, broad resistance did not occur after acquired resistance to a single agent. This provides a therapeutic rationale for combination chemoprevention with agents activating non-cross-resistant pathways.

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