• Journal of Life Science
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• v.31 no.5
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• pp.527-535
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• 2021

Lysosomes are organelles surrounded by membranes that contain acid hydrolases; they degrade proteins, macromolecules, and lipids. According to nutrient conditions, lysosomes act as signaling hubs that regulate intracellular signaling pathways and are involved in the homeostasis of cells. Therefore, the lysosomal dysfunction occurs in various diseases, such as lysosomal storage disease, neurodegenerative diseases, and cancers. Multiple forms of stress can increase lysosomal membrane permeabilization (LMP), resulting in the induction of lysosome-mediated cell death through the release of lysosomal enzymes, including cathepsin, into the cytosol. Here we review the molecular mechanisms of LMP-mediated cell death and the enhancement of sensitivity to anticancer drugs. Induction of partial LMP increases apoptosis by releasing some cathepsins, whereas massive LMP and rupture induce non-apoptotic cell death through release of many cathepsins and generation of ROS and iron. Cancer cells have many drug-accumulating lysosomes that are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. Lysosomal sequestration of hydrophobic weak base anticancer drugs can have a significant impact on their subcellular distribution. Lysosome membrane damage by LMP can overcome resistance to anticancer drugs by freeing captured hydrophobic weak base drugs from lysosomes. Therefore, LMP inducers or lysosomotropic agents can regulate lysosomal integrity and are novel strategies for cancer therapy.

• Journal of Microbiology and Biotechnology
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• v.26 no.4
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• pp.790-798
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• 2016

Chlamydiae, obligate intracellular bacteria, are associated with a variety of human diseases. The chlamydial life cycle undergoes a biphasic development: replicative reticulate bodies (RBs) phase and infectious elementary bodies (EBs) phase. At the end of the chlamydial intracellular life cycle, EBs have to be released to the surrounded cells. Therefore, the interactions between Chlamydiae and cell death pathways could greatly influence the outcomes of Chlamydia infection. However, the underlying molecular mechanisms remain elusive. Here, we investigated host cell death after Chlamydia infection in vitro, in L929 cells, and showed that Chlamydia infection induces cell necrosis, as detected by the propidium iodide (PI)-Annexin V double-staining flow-cytometric assay and Lactate dehydrogenase (LDH) release assay. The production of reactive oxygen species (ROS), an important factor in induction of necrosis, was increased after Chlamydia infection, and inhibition of ROS with specific pharmacological inhibitors, diphenylene iodonium (DPI) or butylated hydroxyanisole (BHA), led to significant suppression of necrosis. Interestingly, live-cell imaging revealed that Chlamydia infection induced lysosome membrane permeabilization (LMP). When an inhibitor upstream of LMP, CA-074-Me, was added to cells, the production of ROS was reduced with concomitant inhibition of necrosis. Taken together, our results indicate that Chlamydia infection elicits the production of ROS, which is dependent on LMP at least partially, followed by induction of host-cell necrosis. To our best knowledge, this is the first live-cell-imaging observation of LMP post Chlamydia infection and report on the link of LMP to ROS to necrosis during Chlamydia infection.