Blockage of Autophagic Flux and Induction of Mitochondria Fragmentation by Paroxetine Hydrochloride in Lung Cancer Cells Promotes Apoptosis via the ROS-MAPK Pathway

Abstract

Cancer cells are characterized by malignant proliferation and aberrant metabolism and are thereby liable to the depletion of nutrients and accumulation of metabolic waste. To maintain cellular homeostasis, cancer cells are prone to upregulating the canonical autophagy pathway. Here, we identified paroxetine hydrochloride (Paxil) as a late autophagy inhibitor and investigated its killing effect on lung cancer cells and with a xenograft mouse model in vivo. Upregulated LC3-II and p62 expression indicated that Paxil inhibited autophagy. Acid-sensitive dyes (e.g., LysoTracker and AO staining) indicated reduced lysosomal acidity following Paxil treatment; consequently, the maturation of the pH-dependent hydroxylases (e.g., cathepsin B and D) substantially declined. Paxil also induced the fragmentation of mitochondria and further intensified ROS overproduction. Since the autophagy pathway was blocked, ROS rapidly accumulated, which activated JNK and p38 kinase. Such activity promoted the localization of Bax, which led to increased mitochondrial outer membrane permeability. The release of Cytochrome c with the loss of the membrane potential triggered a caspase cascade, ultimately leading to apoptosis. In contrast, the clearance of ROS by its scavenger, NAC, rescued Paxil-induced apoptosis accompanied by reduced p38 and JNK activation. Thus, Paxil blocked the autophagic flux and induced the mitochondria-dependent apoptosis via the ROS-MAPK pathway.

Propranolol induced apoptosis and autophagy via the ROS/JNK signaling pathway in Human Ovarian Cancer

“…On one hand, autophagy [33] decomposed long-lived proteins, damaged organelles and other structures by lysosomal hydrolases to promote survival during various stress conditions. On the other hand, autophagic cell [34] was exerted a similar pro-apoptotic effect when excessive autophagy reaches a certain level. Accumulating findings [35] evidenced the complex paradoxical role of autophagy in antitumor chemotherapy.…”

Propranolol induced apoptosis and autophagy via the ROS/JNK signaling pathway in human ovarian cancer

“…On one hand, autophagy [33] decomposed long-lived proteins, damaged organelles and other structures by lysosomal hydrolases to promote survival during various stress conditions. On the other hand, autophagic cell [34] was exerted a similar pro-apoptotic effect when excessive autophagy reaches a certain level. Accumulating ndings [35] evidenced the complex paradoxical role of autophagy in antitumor chemotherapy.…”

Induced Autophagy of Macrophages and the Regulation of Inflammatory Effects by Perovskite Nanomaterial LaNiO3

“…With an excitation at 488 nm, at the acidic environment such as lysosomes/endosomes, AO emits bright red color while it shows green color at the neutral or basic environment such as the cytoplasm and the nucleus. When the lysosomal membrane integrity decreased, the pH will increase and then there was significant color change in the lysosome from red to green or yellow (27). Confocal images for AO staining show that LNO increases lysosomal membrane permeation at 5 µg/ml, in which the fluorescence of lysosomes changed from red to green (Figure 4).…”