Effects of Citrus-derived Diosmetin on Melanoma: Induction of Apoptosis and Autophagy Mediated by PI3K/Akt/mTOR Pathway Inhibition


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Abstract

Background:Diosmetin (DIOS) is a naturally abundant flavonoid and possesses various biological activities that hold promise as an anti-cancer agent. However, the anti-cancer activities and underlying mechanism of DIOS on cutaneous melanoma remain unclear.

Objective:This study seeks to explore the anti-tumor effect and mechanism of DIOS in cutaneous melanoma.

Methods:Here, a variety of in vitro and in vivo experiments, combined with RNA sequencing (RNA-seq), were employed to ascertain the potential anti-cutaneous melanoma capacity and mechanism of DIOS.

Results:The results demonstrated that DIOS considerably impeded cell proliferation and triggered cell apoptosis in a dose- and time-dependent manner. Concurrently, DIOS markedly elevated the expression of pro-apoptotic proteins (Cleaved caspase-3, Bax, Cleaved PARP, and Cleaved caspase-9) and downregulated the expression of Bcl-2. Additionally, DIOS markedly upregulated the protein expressions of LC3B-II and Atg5, while downregulating p62 protein expression. Notably, pre-treatment with an autophagy inhibitor significantly inhibited DIOSinduced cell apoptosis and autophagy. Mechanistically, DIOS was identified to repress the PI3K/Akt/mTOR signaling pathway by western blot analyses and RNA-seq. Finally, in vivo experiments using a syngeneic mouse model confirmed the anti-tumor effect of DIOS, which exhibited high levels of apoptosis and autophagy.

Conclusion:These findings propose that DIOS acts as a potential melanoma therapy that exerts its anti-tumor effects by triggering apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathway.

About the authors

jie Li

Shanghai Skin Disease Clinical College, The Fifth Clinical Medical College, Anhui Medical University

Email: info@benthamscience.net

Mingyuan Xu

Shanghai Skin Disease Hospital, Tongji University School of Medicine

Email: info@benthamscience.net

Nanhui Wu

Shanghai Skin Disease Hospital, Tongji University School of Medicine

Email: info@benthamscience.net

Fei Wu

Shanghai Skin Disease Hospital, Tongji University School of Medicine

Email: info@benthamscience.net

Jiashe Chen

Shanghai Skin Disease Hospital, Tongji University School of Medicine

Email: info@benthamscience.net

Xiaoxiang Xu

Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai Skin Disease Hospital

Author for correspondence.
Email: info@benthamscience.net

Fei Tan

Shanghai Skin Disease Clinical College, The Fifth Clinical Medical College, Anhui Medical University

Author for correspondence.
Email: info@benthamscience.net

Yeqiang Liu

Shanghai Skin Disease Clinical College, The Fifth Clinical Medical College, Anhui Medical University

Author for correspondence.
Email: info@benthamscience.net

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