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A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

Oncogene volume 24, pages 4257–4270 (2005)Cite this article

Abstract

Retinoid-related molecules are important potential agents for the treatment of cancer. In the present study, we test the effect of a novel retinoid-related ligand, AGN193198 (4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-prophenyl] benzoic acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)- or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR- or RXR receptor-selective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclin-dependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.

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Abbreviations

RAR:

retinoid acid receptors

RXR:

retinoid X receptors

cdk:

cyclin-dependent kinase

RRM:

retinoid-related molecule

PARP:

poly(ADP-ribose) polymerase

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Acknowledgements

This work utilized the facilities of the Skin Diseases Research Center of Northeast Ohio (NIH, AR39750) and was partially supported by Allergan Inc.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106-4970, USA

    Sivaprakasam Balasubramanian & Richard L Eckert

  2. Department of Chemistry, Allergan Inc., Irvine, CA, 92623, USA

    Roshantha A S Chandraratna

  3. Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106-4970, USA

    Richard L Eckert

  4. Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, 44106-4970, USA

    Richard L Eckert

  5. Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106-4970, USA

    Richard L Eckert

  6. Department of Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106-4970, USA

    Richard L Eckert

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  1. Sivaprakasam Balasubramanian
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Correspondence to Richard L Eckert.

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Balasubramanian, S., Chandraratna, R. & Eckert, R. A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis. Oncogene 24, 4257–4270 (2005). https://doi.org/10.1038/sj.onc.1208586

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