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Suppressing ROS‐TFE3‐dependent autophagy enhances ivermectin‐induced apoptosis in human melanoma cells
Author(s) -
Deng Faming,
Xu Qian,
Long Juan,
Xie Hongfu
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27490
Subject(s) - autophagy , apoptosis , melanoma , cancer research , ivermectin , tfe3 , microbiology and biotechnology , microphthalmia associated transcription factor , chemistry , biology , genetics , transcription factor , zoology , gene , enhancer
Melanoma is an aggressive skin malignancy with a high mortality rate; however, successful treatment remains a clinical challenge. Ivermectin, a broad‐spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to its observed antitumor effects. However, the molecular mechanisms of ivermectin remain poorly understood. In the current study, we tested the involvement of autophagy in the ivermectin mechanism of action in human melanoma cells. We exposed SK‐MEL‐28 cells to different concentrations of ivermectin (2.5, 5, and 10 μM) for 24 hours. Here, ivermectin‐induced apoptosis, as evidenced by the upregulation of cleaved poly (ADP‐ribose) polymerase, BAX expression, and caspase‐3 activity and downregulation of BCL‐2 expression. In line with the apoptosis response, ivermectin triggered autophagy. Pharmacological or genetic inhibition of autophagy further sensitized SK‐MEL‐28 cells to ivermectin‐induced apoptosis. Mechanistically, ivermectin‐induced TFE3 (Ser321) dephosphorylation, activated TFE3 nuclear translocation and increased TFE3 reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy‐related genes, and subsequently, initiated autophagy in SK‐MEL‐28 cells. Moreover, N ‐acetyl‐cysteine, an reactive oxygen species (ROS) scavenger, abrogated the effects of ivermectin on TFE3‐dependent autophagy. Taken together, we demonstrated that ivermectin increases TFE3‐dependent autophagy through ROS signaling pathways in human melanoma cells and that inhibiting autophagy enhances ivermectin‐induced apoptosis in human melanoma cells.