Src mediates extracellular signal‐regulated kinase 1/2 activation and autophagic cell death induced by cardiac glycosides in human non‐small cell lung cancer cell lines
Identifieur interne : 000F24 ( Main/Exploration ); précédent : 000F23; suivant : 000F25Src mediates extracellular signal‐regulated kinase 1/2 activation and autophagic cell death induced by cardiac glycosides in human non‐small cell lung cancer cell lines
Auteurs : Yan Wang [République populaire de Chine] ; Yuechen Zhan [République populaire de Chine] ; Rong Xu [République populaire de Chine] ; Rongguang Shao [République populaire de Chine] ; Jiandong Jiang [République populaire de Chine] ; Zhen Wang [République populaire de Chine]Source :
- Molecular Carcinogenesis [ 0899-1987 ] ; 2015-07.
Abstract
Aberrant Na+/K+‐ATPases (NKA) expression is closely related to the incidence and development of cancer, making NKA targeted cancer therapy more intriguing. Cardiac glycosides (CGs) belong to NKA inhibitors and possess potent anti‐cancer properties in many cancers. Our previous work demonstrates that CGs family member digoxin or ouabain induces autophagic cell death in human non‐small cell lung cancer (NSCLC) cell lines through regulation of both mammalian target of rapamycin and extracellular signal‐regulated kinase 1/2 (ERK1/2) pathway. However, what acts as an upstream regulator of ERK1/2 activation during autophagy induction remains obscure. In the present study, the role of Src in the ERK1/2 signaling pathway as well as autophagic cell death induced by either digoxin or ouabain was examined in A549 and H460 cells. Src is significantly activated simultaneously with mitogen‐activated protein kinase kinase 1/2 (MEK1/2) and ERK1/2 activation upon the drug treatment. Moreover, Src inhibitor PP2 could block either drug induced MEK1/2 and ERK1/2 phosphorylation, together with autophagic phenotypes in the cells. Knockdown of Src with siRNA causes the similar effect as PP2, both of which markedly alleviate the drugs' cytotoxicity. In addition, increased levels of intracellular reactive oxygen species (ROS) are found to be involved in Src mediated autophagy. Together, this work provides evidences showing that Src mediates MEK1/2 and ERK1/2 pathway as well as ROS generation, and regulates autophagic cell death induced by the cardiac glycosides. These observations may further help understand the molecular mechanisms of autophagy induced by NKA inhibitors in NSCLC cells. © 2014 Wiley Periodicals, Inc.
Url:
DOI: 10.1002/mc.22147
Affiliations:
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Cardiac glycosides (CGs) belong to NKA inhibitors and possess potent anti‐cancer properties in many cancers. Our previous work demonstrates that CGs family member digoxin or ouabain induces autophagic cell death in human non‐small cell lung cancer (NSCLC) cell lines through regulation of both mammalian target of rapamycin and extracellular signal‐regulated kinase 1/2 (ERK1/2) pathway. However, what acts as an upstream regulator of ERK1/2 activation during autophagy induction remains obscure. In the present study, the role of Src in the ERK1/2 signaling pathway as well as autophagic cell death induced by either digoxin or ouabain was examined in A549 and H460 cells. Src is significantly activated simultaneously with mitogen‐activated protein kinase kinase 1/2 (MEK1/2) and ERK1/2 activation upon the drug treatment. Moreover, Src inhibitor PP2 could block either drug induced MEK1/2 and ERK1/2 phosphorylation, together with autophagic phenotypes in the cells. Knockdown of Src with siRNA causes the similar effect as PP2, both of which markedly alleviate the drugs' cytotoxicity. In addition, increased levels of intracellular reactive oxygen species (ROS) are found to be involved in Src mediated autophagy. Together, this work provides evidences showing that Src mediates MEK1/2 and ERK1/2 pathway as well as ROS generation, and regulates autophagic cell death induced by the cardiac glycosides. These observations may further help understand the molecular mechanisms of autophagy induced by NKA inhibitors in NSCLC cells. © 2014 Wiley Periodicals, Inc.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country><settlement><li>Pékin</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Wang, Yan" sort="Wang, Yan" uniqKey="Wang Y" first="Yan" last="Wang">Yan Wang</name></noRegion><name sortKey="Jiang, Jiandong" sort="Jiang, Jiandong" uniqKey="Jiang J" first="Jiandong" last="Jiang">Jiandong Jiang</name><name sortKey="Jiang, Jiandong" sort="Jiang, Jiandong" uniqKey="Jiang J" first="Jiandong" last="Jiang">Jiandong Jiang</name><name sortKey="Jiang, Jiandong" sort="Jiang, Jiandong" uniqKey="Jiang J" first="Jiandong" last="Jiang">Jiandong Jiang</name><name sortKey="Shao, Rongguang" sort="Shao, Rongguang" uniqKey="Shao R" first="Rongguang" last="Shao">Rongguang Shao</name><name sortKey="Wang, Yan" sort="Wang, Yan" uniqKey="Wang Y" first="Yan" last="Wang">Yan Wang</name><name sortKey="Wang, Zhen" sort="Wang, Zhen" uniqKey="Wang Z" first="Zhen" last="Wang">Zhen Wang</name><name sortKey="Wang, Zhen" sort="Wang, Zhen" uniqKey="Wang Z" first="Zhen" last="Wang">Zhen Wang</name><name sortKey="Xu, Rong" sort="Xu, Rong" uniqKey="Xu R" first="Rong" last="Xu">Rong Xu</name><name sortKey="Zhan, Yuechen" sort="Zhan, Yuechen" uniqKey="Zhan Y" first="Yuechen" last="Zhan">Yuechen Zhan</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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