Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

Li, I‐Hsun; Shih, Jui‐Hu; Yeh, Ting-Yin; Lin, Hung‐Che; Chen, Minghua; Huang, Yuahn-Sieh

doi:10.1021/acs.chemrestox.9b00437

Cited by 7 publications

(5 citation statements)

References 54 publications

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“…3,4-methylenedioxymethamphetamine (MDMA) is a drug of abuse that can have more severe effects in certain environmental conditions, including elevated temperatures 51 . SH-SY5Y cells have been used previously to study the effects of MDMA, so we wanted to examine whether MDMA affected ER stress and exodosis 52, 53 . We observed a marked increase in BiP expression in hyperthermic conditions when MDMA was present, although ERdj4 and ASNS levels were not changed by the presence of MDMA (Fig.…”

Section: Resultsmentioning

confidence: 99%

Caffeine and MDMA (ecstasy) exacerbate ER stress triggered by hyperthermia

Harvey

2022

Preprint

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Drugs of abuse can cause local and systemic hyperthermia, a known trigger of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Another trigger of ER stress and UPR is ER calcium depletion which causes ER exodosis, the secretion of ER resident proteins. Club drugs such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) can create hyperthermic conditions in the brain and cause toxicity that is affected by the environmental temperature and the presence of other drugs, such as caffeine. Here we examine the secretion of ER resident proteins and activation of the UPR under combined exposure to MDMA and caffeine in a cellular model of hyperthermia. We show that hyperthermia triggers the secretion of normally ER resident proteins and that this aberrant protein secretion is potentiated by the presence of MDMA, caffeine, or a combination of the two drugs. Hyperthermia activates the UPR but the addition of MDMA or caffeine does not alter canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased BiP/Grp78 mRNA levels in MDMA-treated cells exposed to hyperthermia. These findings suggest that club drug use under hyperthermic conditions exacerbates disruption of ER proteostasis contributing to cellular toxicity.

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Section: Resultsmentioning

confidence: 99%

Caffeine and MDMA (ecstasy) exacerbate ER stress triggered by hyperthermia

Harvey

2022

Preprint

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“…Several studies have shown that autophagosome accumulation caused by drug blocking of autophagic flux leads to tumor cell death [62][63][64].…”

Section: Discussionmentioning

confidence: 99%

APY0201 Represses Tumor Growth through Inhibiting Autophagy in Gastric Cancer Cells

Jin

Zhang

et al. 2022

Journal of Oncology

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Gastric cancer (GC) is one of the most common cancers globally. There are currently few effective chemotherapeutic drugs available for GC patients. The inhibitors of phosphatidylinositol kinase containing an FYVE finger structure (PIKfyve) have shown significant anticancer effects in several types of cancers, but their effectiveness in GC remains unknown. In this study, we investigate the effect of APY0201, an inhibitor of PIKfyve, on GC tumor growth and its mechanism of action. It was found that APY0201 inhibited GC cell proliferation in in vitro GC cell model, organoid model, and in vivo xenograft tumor model. Through analyzing cell autophagy, we found that APY0201 might block autophagic flux by impairing lysosome degradation function of GC cells, inducing the accumulation of autophagosomes, thus causing the inhibition of GC cell proliferation. We also found that APY0201 induced G1/S phase arrest in GC cells. Importantly, APY0201 was also effective in inducing repression of autophagy and cell cycle arrest in the mouse tumor xenograft. Our results suggest that APY0201 could be a new promising therapeutic option for GC.

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“…In addition, the present study found that BITC increased the size of the acidic vesicles in AGS cells and upregulated a major lysosomal surface protein; LAMP2, suggesting lysosomal swelling. Enlarged lysosomes and LAMP2 upregulation are known to contribute to lysosomal dysfunction ( Wang et al ., 2018 ; Li et al ., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Benzyl Isothiocyanate-Induced Cytotoxicity via the Inhibition of Autophagy and Lysosomal Function in AGS Cells

Choi

Khing

et al. 2022

Biomol Ther (Seoul)

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Gastric adenocarcinoma is among the top causes of cancer-related death and is one of the most commonly diagnosed carcinomas worldwide. Benzyl isothiocyanate (BITC) has been reported to inhibit the gastric cancer metastasis. In our previous study, BITC induced apoptosis in AGS cells. The purpose of the present study was to investigate the effect of BITC on autophagy mechanism in AGS cells. First, the AGS cells were treated with 5, 10, or 15 µM BITC for 24 h, followed by an analysis of the autophagy mechanism. The expression level of autophagy proteins involved in different steps of autophagy, such as LC3B, p62/SQSTM1, Atg5-Atg12, Beclin1, p-mTOR/mTOR ratio, and class III PI3K was measured in the BITC-treated cells. Lysosomal function was investigated using cathepsin activity and Bafilomycin A1, an autophagy degradation stage inhibitor. Methods including qPCR, western blotting, and immunocytochemistry were employed to detect the protein expression levels. Acridine orange staining and omnicathepsin assay were conducted to analyze the lysosomal function. siRNA transfection was performed to knock down the LC3B gene. BITC reduced the level of autophagy protein such as Beclin 1, class III PI3K, and Atg5-Atg12. BITC also induced lysosomal dysfunction which was shown as reducing cathepsin activity, protein level of cathepsin, and enlargement of acidic vesicle. Overall, the results showed that the BITC-induced AGS cell death mechanism also comprises the inhibition of the cytoprotective autophagy at both initiation and degradation steps.

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Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

Cited by 7 publications

References 54 publications

Caffeine and MDMA (ecstasy) exacerbate ER stress triggered by hyperthermia

Caffeine and MDMA (ecstasy) exacerbate ER stress triggered by hyperthermia

APY0201 Represses Tumor Growth through Inhibiting Autophagy in Gastric Cancer Cells

Benzyl Isothiocyanate-Induced Cytotoxicity via the Inhibition of Autophagy and Lysosomal Function in AGS Cells

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