title: PIG7 promotes leukemia cell chemosensitivity via lysosomal membrane permeabilization.
abstract: PIG7 localizes to lysosomal membrane in leukemia cells. Our previous work has shown that transduction of pig7 into a series of leukemia cell lines did not result in either apoptosis or differentiation of most tested cell lines. Interestingly, it did significantly sensitize these cell lines to chemotherapeutic drugs. Here, we further investigated the mechanism underlying pig7-induced improved sensitivity of acute leukemia cells to chemotherapy. Our results demonstrated that the sensitization effect driven by exogenous pig7 was more effective in drug-resistant leukemia cell lines which had lower endogenous pig7 expression. Overexpression of pig7 did not directly activate the caspase apoptotic pathway, but decreased the lysosomal stability. The expression of pig7 resulted in lysosomal membrane permeabilization (LMP) and lysosomal protease (e.g. cathepsin B, D, L) release. Moreover, we also observed increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (ΔΨm) induced by pig7. Some autophagy markers such as LC3I/II, ATG5 and Beclin-1, and necroptosis maker MLKL were also stimulated. However, intrinsic antagonism such as serine/cysteine protease inhibitors Spi2A and Cystatin C prevented downstream effectors from triggering leukemia cells, which were only on the "verge of apoptosis". When combined with chemotherapy, LMP increased and more proteases were released. Once this process was beyond the limit of intrinsic antagonism, it induced programmed cell death cooperatively via caspase-independent and caspase-dependent pathways.
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Jiazhuo
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Leiwen
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; C118738:LITAF protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D020169:Caspases
keywords: LMP; PIG7; ROS; cathepsin; chemosensitivity