Formosanin C induces autophagy-mediated apoptosis in multiple myeloma cells through the PI3K/AKT/mTOR signaling pathway

ABSTRACT

Objectives

Multiple myeloma (MM) is an incurable plasma cell malignancy associated with poor survival. Novel therapeutic drugs are urgently needed to improve MM therapy and patient outcomes. This study aimed to investigate the effect of formosanin C (FC), a Chinese medicine monomer, on MM in vitro and disclose the underlying molecular mechanism.

Methods

The effect of FC on the viability, proliferation, apoptosis, and autophagy of MM cell lines (NCI-H929 and ARP1) was studied through CCK-8, colony formation, flow cytometry, GFP-LC3, and western blotting assays, respectively. A pharmacological approach and network pharmacology technology were implemented to explore the potential mechanisms of the action of FC on MM cells.

Results

FC efficiently suppressed the viability and colony-forming capacity, but promoted the number of autophagic vacuoles with GFP-LC3 localization and the percentage of apoptotic cells in MM cells. Additionally, FC significantly increased the levels of the autophagy-related proteins LC3-Ⅱ and Beclin 1, as well as the apoptosis-related proteins Bax and cleaved caspase-3, but blocked the expression of the proapoptotic protein Bcl-2 in the cells; these effects were reversed by an inhibitor of autophagy, 3-methyladenine. What's more, we found that the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was involved in the FC-mediated inhibition of MM. Pharmacological inhibition of this pathway dramatically relieved FC-triggered excessive expression of autophagy-related proteins and rescued MM cells from FC-induced apoptosis.

Conclusion

Our findings indicate that FC exhibits an anti-MM effect by activating cell autophagy through the PI3K/AKT/mTOR signaling pathway.

KEYWORDS:

• Formosanin C
• multiple myeloma
• autophagy
• apoptosis
• PI3K/AKT/mTOR

Acknowledgments

We would like to express our great appreciation and gratitude to Professor Ye Yang, Nanjing University of Chinese Medicine, for providing MM cell lines.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by the Project of Jiangsu Provincial Medical Innovation Team (CXTDA2017046), the Natural Science Foundation of Jiangsu Province (BK20210028), and the Medical Science and Technique Development Foundation of Nanjing Department of Health (YKK20083).