Abstract
BackgroundGarcinia subelliptica Merr. is a multipurpose coastal tree, the potential medicinal effects of which have been studied, including cancer suppression. Here, we present evidence that the ethanol extract of G. subelliptica Merr. (eGSM) induces autophagy in human lung adenocarcinoma cells.MethodsTwo different human lung adenocarcinoma cell lines, A549 and SNU2292, were treated with varying amounts of eGSM. Cytotoxicity elicited by eGSM was assessed by MTT assay and PARP degradation. Autophagy in A549 and SNU2292 was determined by western blotting for AMPK, mTOR, ULK1, and LC3. Genetic deletion of AMPKα in HEK293 cells was carried out by CRISPR.ResultseGSM elicited cytotoxicity, but not apoptosis, in A549 and SNU2292 cells. eGSM increased LC3-II production in both A549 and, more extensively, SNU2292, suggesting that eGSM induces autophagy. In A549, eGSM activated AMPK, an essential autophagy activator, but not suppressed mTOR, an autophagy blocker, suggesting that eGSM induces autophagy by primarily activating the AMPK pathway in A549. By contrast, eGSM suppressed mTOR activity without activating AMPK in SNU2292, suggesting that eGSM induces autophagy by mainly suppressing mTOR in SNU2292. In HEK293 cells lacking AMPKα expression, eGSM increased LC3-II production, confirming that the autophagy induced by eGSM can occur without the AMPK pathway.ConclusionOur findings suggest that eGSM induces autophagy by activating AMPK or suppressing mTOR pathways, depending on cell types.
Highlights
Garcinia subelliptica Merr. is a coastal tree species found in Japan, China, Taiwan, India, Sri Lanka, and the Philippines [1]
One million A549 cells were treated with increasing amounts of extract of G. subelliptica Merr. (eGSM) for 16 h, and the cytotoxicity elicited by eGSM was determined by MTT assay
The viability of A549 cells was further reduced as the amount of eGSM increased; the cytotoxicity at 200 μg/ml was comparable to doxorubicin (2 μg/ml)
Summary
Garcinia subelliptica Merr. is a coastal tree species found in Japan, China, Taiwan, India, Sri Lanka, and the Philippines [1]. Garcinielliptones were reported to inhibit the release of β-glucuronidase and lysozyme [3] They suppress superoxide formation from activated neutrophils and peripheral mast cells [4]. The activated mTOR senses energy-rich environmental cues, prompting anabolism and suppressing autophagy by phosphorylating ULK1 at S757 [13]. In a metabolically adverse environment where glucose or amino acids are limited and catabolism is required for cell survival [14], AMPK becomes activated and increases autophagy while suppressing mTOR activity, resulting in enhanced catabolism [15]. ULK1 phosphorylated at these sites triggers autophagosome formation, making autophagy start [14]. Once ULK1 becomes active, as indicated by phosphorylation at S317 and but not at S757, autophagy process initiates to form autophagosomes [18]. We present evidence that the ethanol extract of G. subelliptica Merr. (eGSM) induces autophagy in human lung adenocarcinoma cells
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