Blockage of Autophagic Flux and Induction of Mitochondria Fragmentation by Paroxetine Hydrochloride in Lung Cancer Cells Promotes Apoptosis via the ROS-MAPK Pathway
Identifieur interne : 000202 ( Main/Exploration ); précédent : 000201; suivant : 000203Blockage of Autophagic Flux and Induction of Mitochondria Fragmentation by Paroxetine Hydrochloride in Lung Cancer Cells Promotes Apoptosis via the ROS-MAPK Pathway
Auteurs : Kun Wang [République populaire de Chine] ; Qing Gong [République populaire de Chine] ; Yujuan Zhan [République populaire de Chine] ; Bonan Chen [République populaire de Chine] ; Ting Yin [République populaire de Chine] ; Yuhua Lu [République populaire de Chine] ; Yilin Zhang [République populaire de Chine] ; Huiqi Wang [République populaire de Chine] ; Junzi Ke [République populaire de Chine] ; Biaoyan Du [République populaire de Chine] ; Xiaodong Liu [Hong Kong] ; Jianyong Xiao [République populaire de Chine]Source :
- Frontiers in Cell and Developmental Biology [ 2296-634X ] ; 2020.
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
Url:
DOI: 10.3389/fcell.2019.00397
PubMed: 32039209
PubMed Central: 6987457
Affiliations:
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Pathology, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Yilin" sort="Zhang, Yilin" uniqKey="Zhang Y" first="Yilin" last="Zhang">Yilin Zhang</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Pathology, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Huiqi" sort="Wang, Huiqi" uniqKey="Wang H" first="Huiqi" last="Wang">Huiqi Wang</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ke, Junzi" sort="Ke, Junzi" uniqKey="Ke J" first="Junzi" last="Ke">Junzi Ke</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Du, Biaoyan" sort="Du, Biaoyan" uniqKey="Du B" first="Biaoyan" last="Du">Biaoyan Du</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Pathology, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Xiaodong" sort="Liu, Xiaodong" uniqKey="Liu X" first="Xiaodong" last="Liu">Xiaodong Liu</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong</institution>,<addr-line>Shatin</addr-line>,<country>Hong Kong</country></nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Xiao, Jianyong" sort="Xiao, Jianyong" uniqKey="Xiao J" first="Jianyong" last="Xiao">Jianyong Xiao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32039209</idno><idno type="pmc">6987457</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987457</idno><idno type="RBID">PMC:6987457</idno><idno type="doi">10.3389/fcell.2019.00397</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000527</idno><idno type="wicri:explorRef" 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last="Wang">Kun Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Pathology, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gong, Qing" sort="Gong, Qing" uniqKey="Gong Q" first="Qing" last="Gong">Qing Gong</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zhan, Yujuan" sort="Zhan, Yujuan" uniqKey="Zhan Y" first="Yujuan" last="Zhan">Yujuan Zhan</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Bonan" sort="Chen, Bonan" uniqKey="Chen B" first="Bonan" last="Chen">Bonan Chen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yin, Ting" sort="Yin, Ting" uniqKey="Yin T" first="Ting" last="Yin">Ting Yin</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lu, Yuhua" sort="Lu, Yuhua" uniqKey="Lu Y" first="Yuhua" last="Lu">Yuhua Lu</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Pathology, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Yilin" sort="Zhang, Yilin" uniqKey="Zhang Y" first="Yilin" last="Zhang">Yilin Zhang</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Pathology, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Huiqi" sort="Wang, Huiqi" uniqKey="Wang H" first="Huiqi" last="Wang">Huiqi Wang</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ke, Junzi" sort="Ke, Junzi" uniqKey="Ke J" first="Junzi" last="Ke">Junzi Ke</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Du, Biaoyan" sort="Du, Biaoyan" uniqKey="Du B" first="Biaoyan" last="Du">Biaoyan Du</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Pathology, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Xiaodong" sort="Liu, Xiaodong" uniqKey="Liu X" first="Xiaodong" last="Liu">Xiaodong Liu</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong</institution>,<addr-line>Shatin</addr-line>,<country>Hong Kong</country></nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Xiao, Jianyong" sort="Xiao, Jianyong" uniqKey="Xiao J" first="Jianyong" last="Xiao">Jianyong Xiao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Biochemistry, Guangzhou University of Chinese Medicine</institution>,<addr-line>Guangzhou</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Frontiers in Cell and Developmental Biology</title><idno type="eISSN">2296-634X</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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 <italic>in vivo</italic>. 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Asakura, T" uniqKey="Asakura T">T. Asakura</name></author><author><name sortKey="Maeda, K" uniqKey="Maeda K">K. Maeda</name></author><author><name sortKey="Omi, H" uniqKey="Omi H">H. Omi</name></author><author><name sortKey="Matsudaira, H" uniqKey="Matsudaira H">H. Matsudaira</name></author><author><name sortKey="Ohkawa, K" uniqKey="Ohkawa K">K. Ohkawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ashrafi, G" uniqKey="Ashrafi G">G. 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