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Inhibition of ROS production, autophagy or apoptosis signaling reversed the anticancer properties of Antrodia salmonea in triple-negative breast cancer (MDA-MB-231) cells

Author:
Chang, Chia-Ting, Korivi, Mallikarjuna, Huang, Hui-Chi, Thiyagarajan, Varadharajan, Lin, Kai-Yuan, Huang, Pei-Jane, Liu, Jer-Yuh, Hseu, You-Cheng, Yang, Hsin-Ling
Source:
Food and chemical toxicology 2017 v.103 pp. 1-17
ISSN:
0278-6915
Subject:
Antrodia, DNA, DNA fragmentation, acetylcysteine, antineoplastic activity, apoptosis, autophagy, bioluminescence, breast neoplasms, cell viability, culture media, death, humans, image analysis, medicinal fungi, mice, mitochondria, necrosis, signal transduction, toxicology, Taiwan
Abstract:
We investigated the in vitro and in vivo anticancer properties of Antrodia salmonea (AS), a well-known edible/medicinal mushroom in Taiwan, on human triple-negative breast cancer (MDA-MB-231) cells and xenografted nude mice; and revealed the underlying molecular mechanisms involved in autophagic- and apoptotic-cell death. Treatment of MDA-MB-231 cells with fermented culture broth of AS (0–200 μg/mL) inhibited cell viability/growth. AS-induced autophagy was evidenced via increased LC3-II accumulation, GFP-LC3 puncta and AVOs formation in MDA-MB-231 cells. These events are associated with increased ATG7, decreased p-mTOR, vanished SQSTM1/p62 expressions and dysregulated Beclin-1/Bcl-2 ratio. AS-induced apoptosis/necrosis through increased DNA fragmentation, Annexin-V/PI stained cells and Bax expression. Both mitochondrial (caspase-9/caspase-3/PARP) and death-receptor (caspase-8/FasL/Fas) signaling pathways are involved in execution of apoptosis. Interestingly, blockade of AS-induced ROS production by N-acetylcysteine pretreatment substantially attenuated AS-induced autophagy, mitochondrial dysfunction and autophagic/apoptotic-cell death. Inhibition of apoptosis by Z-VAD-FMK suppressed AS-induced autophagic-death (decreased LC3-II/AVOs). Similarly, inhibition of autophagy by 3-methyladenine/chloroquine diminished AS-induced apoptosis (decreased DNA fragmentation/caspase-3) in MDA-MB-231 cells. Bioluminescence imaging further confirmed that AS inhibited breast tumor growth in living MDA-MB-231-luciferase-injected nude mice. Taken together, AS crucially involved in execution/propagation of autophagic- or apoptotic-death of MDA-MB-231 cells, and decreased tumor growth in xenografted nude mice.
Agid:
5639021