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Chrysin suppresses achaete-scute complex-like 1 and alters the neuroendocrine phenotype of carcinoids

Cancer Gene Therapy volume 22, pages 496–505 (2015)Cite this article

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Abstract

Carcinoids are neuroendocrine neoplasms that cause significant morbidity and mortality and for which few effective therapies are available. Given the recent identification of the anticancer flavonoid chrysin, we sought to investigate its therapeutic potential in carcinoids. Here we report chrysin’s ability to modulate the achaete-scute complex-like 1 (ASCL1), a neuroendocrine-specific transcription factor highly implicated in the malignant phenotype of carcinoids and other neuroendocrine cancers. Moreover, we elucidate the role of ASCL1 in carcinoid growth and bioactivity. Treatment of two carcinoid cell lines (BON and H727) with varying chrysin concentrations suppressed cell proliferation, while reducing expression of ASCL1 and the neuroendocrine biomarker chromogranin A (CgA), demonstrated by western blotting. Propidium iodide and phycoerythrin AnnexinV/7-aminoactinomycin D staining and sorting following chrysin treatment revealed S/G2 phase arrest and apoptosis, respectively. This was corroborated by chrysin-induced cleavage of caspase-3 and poly ADP-ribose polymerase and activation of p21Waf1/Cip1. Furthermore, direct ASCL1 knockdown with an ASCL1-specific small interfering RNA inhibited CgA and synaptophysin expression as well as carcinoid proliferation, while also reducing cyclin B1 and D1 and increasing p21Waf1/Cip1 and p27Kip1 expression, suggesting an arrest of the cell cycle. Collectively, these findings warrant the deliberation of targeted ASCL1 suppression by chrysin or other agents as a therapeutic approach for carcinoid management.

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Acknowledgements

This research was supported under the NIH National Research Service Award T32 GM07215 (to YRS), the Howard Hughes Medical Institute Medical Research Fellows Program (to YRS), a research scholarship from the American College of Surgeons (to BZD), a NIH grant R01 CA121115 (to HC), the American Cancer Society MEN2 Thyroid Cancer Professorship 120319-RPM-11-080-01-TBG and Research Scholar Award RSGM TBE-121413 (to HC) and the Layton F. Rikkers, MD, Chair in Surgical Leadership Professorship (to HC).

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Authors and Affiliations

  1. Department of Surgery, Endocrine Surgery Research Laboratories, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Y R Somnay, B Z Dull, J Eide, R Jaskula-Sztul & H Chen

  2. University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI, USA

    Y R Somnay, B Z Dull, J Eide, R Jaskula-Sztul & H Chen

  3. Department of Surgery, University of Alabama-Birmingham, Birmingham, AL, USA

    R Jaskula-Sztul & H Chen

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Somnay, Y., Dull, B., Eide, J. et al. Chrysin suppresses achaete-scute complex-like 1 and alters the neuroendocrine phenotype of carcinoids. Cancer Gene Ther 22, 496–505 (2015). https://doi.org/10.1038/cgt.2015.49

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