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Chrysin suppresses achaete-scute complex-like 1 and alters the neuroendocrine phenotype of carcinoids
Y R Somnay1,2, B Z Dull1,2, J Eide1,2
1Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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 p21(Waf1/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 p21(Waf1/Cip1) and p27(Kip1) 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.
Insights
The flavonoid chrysin inhibits carcinoid tumor growth by suppressing the achaete-scute complex-like 1 (ASCL1) transcription factor. This targeted approach induces cell cycle arrest and apoptosis, offering a potential new therapy for neuroendocrine cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Carcinoids are neuroendocrine neoplasms with limited therapeutic options.
- The transcription factor achaete-scute complex-like 1 (ASCL1) is crucial for neuroendocrine cancer malignancy.
- Chrysin, an anticancer flavonoid, shows potential for therapeutic intervention.
Purpose of the Study:
- To investigate the therapeutic potential of chrysin in carcinoid tumors.
- To elucidate the role of ASCL1 in carcinoid cell proliferation and bioactivity.
- To determine if chrysin modulates ASCL1 expression and downstream pathways.
Main Methods:
- Treatment of carcinoid cell lines (BON, H727) with chrysin.
- Western blotting to assess ASCL1 and chromogranin A (CgA) expression.
- Flow cytometry (propidium iodide, AnnexinV/7-aminoactinomycin D) for cell cycle and apoptosis analysis.
- ASCL1 knockdown using small interfering RNA (siRNA).
Main Results:
- Chrysin suppressed carcinoid cell proliferation and reduced ASCL1 and CgA expression.
- Chrysin induced S/G2 cell cycle arrest and apoptosis, evidenced by caspase-3 and PARP cleavage, and p21 activation.
- ASCL1 knockdown mimicked chrysin's effects, inhibiting proliferation and altering cell cycle regulators (cyclins, p21, p27).
Conclusions:
- Chrysin effectively inhibits carcinoid cell growth and induces apoptosis.
- Targeting ASCL1, a key driver in carcinoids, is a viable therapeutic strategy.
- Chrysin or other ASCL1-targeting agents represent promising avenues for carcinoid management.
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