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Background <p>Costunolide (COS), a sesquiterpene lactone extracted from the roots of <i>Saussurea costus</i>, is known to possess anticancer properties in various cancers, including colon, oral, and lung cancers, but its mechanism of action in skin carcinogenesis has not yet been explored. Present study investigates the chemopreventive mechanism of COS on skin inflammation and carcinogenesis both in vitro and in vivo.</p> Methods <p>The cytotoxicity of COS was examined on a normal murine epidermal cell line, JB6, by treating with COS using the WST-8 assay. Subsequently, the effect of COS on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cellular transformation was assessed through a soft-agar assay. Furtherly, cell cycle and apoptosis analysis and the expression of related proteins were determined via flow cytometry and Western blotting, respectively. The effects of COS on tumor promotion induced by DMBA/TPA treatment and the underlying molecular mechanisms in mouse skin carcinogenesis were identified through H&amp;E staining and immunohistochemical analysis.</p> Results <p>COS significantly inhibited colony growth and number in TPA-induced JB6 cells transformation, arrested the cell cycle at the G2/M phase, increased p21 expression, and decreased cyclin B expression. In addition, COS induced cell apoptosis and increased the related markers expression including cleaved caspase-3 and − 7. COS suppressed the expression of phosphorylated AKT and its downstream signaling proteins and effectively reduced the translocation of phosphorylated NF-κB from the cytosol to the nucleus. Moreover, COS reduced papilloma formation in mouse skin and inhibited hyperplasia and phosphorylated AKT expression in tissues.</p> Conclusion <p>These results demonstrate that COS inhibits TPA-induced cellular transformation and skin carcinogenesis both in vitro and in vivo through the AKT signaling pathway. Our findings suggest the potential of COS as a chemopreventive agent for skin carcinogenesis, highlighting its significance for further investigation in cancer prevention and therapy.</p> Graphical Abstract <p></p>

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Costunolide inhibits the progression of TPA-induced cell transformation and DMBA/TPA-induced skin carcinogenesis by regulation of AKT-mediated signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月20日

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  • Kwanhwan Wi,
  • Sun-Young Hwang,
  • Young-Gwon Kim,
  • Soong-In Lee,
  • Cheol-Jung Lee,
  • Geul Bang,
  • Je-Ho Lee,
  • Mee-Hyun Lee

摘要

Background

Costunolide (COS), a sesquiterpene lactone extracted from the roots of Saussurea costus, is known to possess anticancer properties in various cancers, including colon, oral, and lung cancers, but its mechanism of action in skin carcinogenesis has not yet been explored. Present study investigates the chemopreventive mechanism of COS on skin inflammation and carcinogenesis both in vitro and in vivo.

Methods

The cytotoxicity of COS was examined on a normal murine epidermal cell line, JB6, by treating with COS using the WST-8 assay. Subsequently, the effect of COS on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cellular transformation was assessed through a soft-agar assay. Furtherly, cell cycle and apoptosis analysis and the expression of related proteins were determined via flow cytometry and Western blotting, respectively. The effects of COS on tumor promotion induced by DMBA/TPA treatment and the underlying molecular mechanisms in mouse skin carcinogenesis were identified through H&E staining and immunohistochemical analysis.

Results

COS significantly inhibited colony growth and number in TPA-induced JB6 cells transformation, arrested the cell cycle at the G2/M phase, increased p21 expression, and decreased cyclin B expression. In addition, COS induced cell apoptosis and increased the related markers expression including cleaved caspase-3 and − 7. COS suppressed the expression of phosphorylated AKT and its downstream signaling proteins and effectively reduced the translocation of phosphorylated NF-κB from the cytosol to the nucleus. Moreover, COS reduced papilloma formation in mouse skin and inhibited hyperplasia and phosphorylated AKT expression in tissues.

Conclusion

These results demonstrate that COS inhibits TPA-induced cellular transformation and skin carcinogenesis both in vitro and in vivo through the AKT signaling pathway. Our findings suggest the potential of COS as a chemopreventive agent for skin carcinogenesis, highlighting its significance for further investigation in cancer prevention and therapy.

Graphical Abstract