Garciniagifolone A, derived from Garcinia multiflora fruits, inhibits triple-negative breast cancer cells and organoids growth by targeting CA9

TL;DR

Garciniagifolone A, a compound from Garcinia multiflora fruits, inhibits triple-negative breast cancer growth by targeting a specific protein and inducing cell death.

Contribution

GA is shown to target CA9, dysregulate autophagy, and induce pyroptosis/apoptosis in triple-negative breast cancer.

Findings

GA inhibits TNBC cell proliferation, migration, and invasion in vitro and suppresses tumor growth in vivo.

GA binds to CA9, suppressing the PI3K/AKT/mTOR pathway and inducing early autophagy.

GA causes ROS overproduction, leading to pyroptosis and apoptosis in TNBC cells.

Abstract

The Garcinia multiflora. is not only a delicious fruit that can be consumed directly, but also contains abundant medicinal components in anti-inflammatory and anti-tumor treatments. The objective of this study was to clarify the anti-tumor properties and the underlying mechanism of garciniagifolone A (GA), a polycyclic polyprenylated acylphloroglucinol derived from the edible fruits of Garcinia multiflora, in triple-negative breast cancer (TNBC). Herein, we demonstrated that GA exhibited inhibitory effects on TNBC organoids growth, and suppressed the proliferation, colony formation, migration, and invasion of TNBC cells in vitro. Moreover, GA demonstrated a significant suppression of TNBC growth in vivo without apparent toxicity, and it augmented the anti-tumor efficacy of PTX in both TNBC organoids and xenograft models. GA specifically bound with carbonic anhydrase IX (CA9), a target overexpressed in TNBC and linked to poor prognosis, as confirmed by molecular docking, surface plasmon resonance, and cellular thermal shift assays. Mechanistically, GA binding to CA9 suppresses the PI3K/AKT/mTOR pathway, inducing early-stage autophagy initiation evidenced by increased LC3B-II/I ratio and autophagosomes. However, GA concurrently blocked autophagic flux by inhibiting autophagosome-lysosome fusion, leading to p62 accumulation and reactive oxygen species (ROS) overproduction. Elevated ROS by GA activated the JNK pathway and triggered NLRP3 inflammasome assembly, resulting in caspase-1-mediated cleavage of gasdermin D (GSDMD) and subsequent pyroptosis, alongside caspase-3-dependent apoptosis. Collectively, GA exerted its potent anti-TNBC activity by targeting CA9 to dysregulate autophagy and induce ROS-mediated pyroptosis/apoptosis, presenting a promising low-toxicity therapeutic strategy.

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