PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion

被引：174

作者：

Caino, M. Cecilia ^{[1
,2
]}

Ghosh, Jagadish C. ^{[1
,2
]}

Chae, Young Chan ^{[1
,2
]}

Vaira, Valentina ^{[3
,4
]}

Rivadeneira, Dayana B. ^{[1
,2
]}

Faversani, Alice ^{[4
]}

Rampini, Paolo ^{[5
]}

Kossenkov, Andrew V. ^{[6
]}

Aird, Katherine M. ^{[7
]}

Zhang, Rugang ^{[7
]}

Webster, Marie R. ^{[2
]}

Weeraratna, Ashani T. ^{[2
]}

Bosari, Silvano ^{[4
,8
]}

Languino, Lucia R. ^{[1
,9
]}

Altieri, Dario C. ^{[1
,2
]}

机构：

[1] Wistar Inst Anat & Biol, Prostate Canc Discovery & Dev Program, Philadelphia, PA 19104 USA

[2] Wistar Inst Anat & Biol, Tumor Microenvironm & Metastasis Program, Philadelphia, PA 19104 USA

[3] Ist Nazl Genet Mol Romeo & Enrica Invernizzi, I-20122 Milan, Italy

[4] Fdn Ist Ricovero & Cura Carattere Sci IRCCS Ca Gr, Div Pathol, I-20122 Milan, Italy

[5] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Div Neurosurg, I-20122 Milan, Italy

[6] Wistar Inst Anat & Biol, Ctr Syst & Computat Biol, Philadelphia, PA 19104 USA

[7] Wistar Inst Anat & Biol, Gene Express & Regulat Program, Philadelphia, PA 19104 USA

[8] Univ Milan, Dept Pathophysiol & Organ Transplant, I-20122 Milan, Italy

[9] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 28期

基金：

美国国家卫生研究院;

关键词：

mitochondria; molecular therapy; cytoskeleton; PI3K; cell invasion; CANCER-CELLS; OXIDATIVE-PHOSPHORYLATION; MIGRATION; DYNAMICS; METASTASIS; CHEMOTAXIS; GLYCOLYSIS; ACTIVATION; EXPRESSION; MOTILITY;

D O I：

10.1073/pnas.1500722112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Molecular therapies are hallmarks of "personalized" medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, "spatiotemporal" mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.

引用

页码：8638 / 8643

页数：6

共 48 条

[1]

CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[2]

Mitochondrial trafficking in neurons and the role of the Miro family of GTPase proteins [J].

Birsa, Nicol ;

Norkett, Rosalind ;

Higgs, Nathalie ;

Lopez-Domenech, Guillermo ;

Kittler, Josef T. .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2013, 41 :1525-1531

[3]

Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells [J].

Caino, M. Cecilia ;

Chae, Young Chan ;

Vaira, Valentina ;

Ferrero, Stefano ;

Nosotti, Mario ;

Martin, Nina M. ;

Weeraratna, Ashani ;

O'Connell, Michael ;

Jernigan, Danielle ;

Fatatis, Alessandro ;

Languino, Lucia R. ;

Bosari, Silvano ;

Altieri, Dario C. .

JOURNAL OF CLINICAL INVESTIGATION, 2013, 123 (07) :2907-2920

[4]

Landscape of the mitochondrial Hsp90 metabolome in tumours [J].

Chae, Young Chan ;

Angelin, Alessia ;

Lisanti, Sofia ;

Kossenkov, Andrew V. ;

Speicher, Kaye D. ;

Wang, Huan ;

Powers, James F. ;

Tischler, Arthur S. ;

Pacak, Karel ;

Fliedner, Stephanie ;

Michalek, Ryan D. ;

Karoly, Edward D. ;

Wallace, Douglas C. ;

Languino, Lucia R. ;

Speicher, David W. ;

Altieri, Dario C. .

NATURE COMMUNICATIONS, 2013, 4

[5]

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors [J].

Chakrabarty, Anindita ;

Sanchez, Violeta ;

Kuba, Maria G. ;

Rinehart, Cammie ;

Arteaga, Carlos L. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (08) :2718-2723

[6]

Dynamic Proteomics of Individual Cancer Cells in Response to a Drug [J].

Cohen, A. A. ;

Geva-Zatorsky, N. ;

Eden, E. ;

Frenkel-Morgenstern, M. ;

Issaeva, I. ;

Sigal, A. ;

Milo, R. ;

Cohen-Saidon, C. ;

Liron, Y. ;

Kam, Z. ;

Cohen, L. ;

Danon, T. ;

Perzov, N. ;

Alon, U. .

SCIENCE, 2008, 322 (5907) :1511-1516

[7]

Role of PFKFB3-Driven Glycolysis in Vessel Sprouting [J].

De Bock, Katrien ;

Georgiadou, Maria ;

Schoors, Sandra ;

Kuchnio, Anna ;

Wong, Brian W. ;

Cantelmo, Anna Rita ;

Quaegebeur, Annelies ;

Ghesquiere, Bart ;

Cauwenberghs, Sandra ;

Eelen, Guy ;

Phng, Li-Kun ;

Betz, Inge ;

Tembuyser, Bieke ;

Brepoels, Katleen ;

Welti, Jonathan ;

Geudens, Ilse ;

Segura, Inmaculada ;

Cruys, Bert ;

Bifari, Franscesco ;

Decimo, Ilaria ;

Blanco, Raquel ;

Wyns, Sabine ;

Vangindertael, Jeroen ;

Rocha, Susana ;

Collins, Russel T. ;

Munck, Sebastian ;

Daelemans, Dirk ;

Imamura, Hiromi ;

Devlieger, Roland ;

Rider, Mark ;

Van Veldhoven, Paul P. ;

Schuit, Frans ;

Bartrons, Ramon ;

Hofkens, Johan ;

Fraisl, Peter ;

Telang, Sucheta ;

DeBerardinis, Ralph J. ;

Schoonjans, Luc ;

Vinckier, Stefan ;

Chesney, Jason ;

Gerhardt, Holger ;

Dewerchin, Mieke ;

Carmeliet, Peter .

CELL, 2013, 154 (03) :651-663

[8]

Mitochondrial Localization and the Persistent Migration of Epithelial Cancer cells [J].

Desai, Salil P. ;

Bhatia, Sangeeta N. ;

Toner, Mehmet ;

Irimia, Daniel .

BIOPHYSICAL JOURNAL, 2013, 104 (09) :2077-2088

[9]

Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis [J].

Ebos, John M. L. ;

Lee, Christina R. ;

Cruz-Munoz, William ;

Bjarnason, Georg A. ;

Christensen, James G. ;

Kerbel, Robert S. .

CANCER CELL, 2009, 15 (03) :232-239

[10]

The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism [J].

Engelman, Jeffrey A. ;

Luo, Ji ;

Cantley, Lewis C. .

NATURE REVIEWS GENETICS, 2006, 7 (08) :606-619

← 1 2 3 4 5 →