Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer

Jun Hyoung Park; Sajna Vithayathil; Santosh Kumar; Pi Lin Sung; Lacey Elizabeth Dobrolecki; Vasanta Putluri; Vadiraja B. Bhat; Salil Kumar Bhowmik; Vineet Gupta; Kavisha Arora; Danli Wu; Efrosini Tsouko; Yiqun Zhang; Suman Maity; Taraka R. Donti; Brett H. Graham; Daniel E. Frigo; Cristian Coarfa; Patricia Yotnda; Nagireddy Putluri; Arun Sreekumar; Michael T. Lewis; Chad J. Creighton; Lee Jun C Wong; Benny Abraham Kaipparettu

doi:10.1016/j.celrep.2016.02.004

Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer

Jun Hyoung Park, Sajna Vithayathil, Santosh Kumar, Pi Lin Sung, Lacey Elizabeth Dobrolecki, Vasanta Putluri, Vadiraja B. Bhat, Salil Kumar Bhowmik, Vineet Gupta, Kavisha Arora, Danli Wu, Efrosini Tsouko, Yiqun Zhang, Suman Maity, Taraka R. Donti, Brett H. Graham, Daniel E. Frigo, Cristian Coarfa, Patricia Yotnda, Nagireddy PutluriArun Sreekumar, Michael T. Lewis, Chad J. Creighton, Lee Jun C Wong, Benny Abraham Kaipparettu

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Abstract

Transmitochondrial cybrids and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in triple-negative breast cancer (TNBC). Analysis of cybrids and established breast cancer (BC) cell lines showed that metastatic TNBC maintains high levels of ATP through fatty acid β oxidation (FAO) and activates Src oncoprotein through autophosphorylation at Y419. Manipulation of FAO including the knocking down of carnitine palmitoyltransferase-1A (CPT1) and 2 (CPT2), the rate-limiting proteins of FAO, and analysis of patient-derived xenograft models confirmed the role of mitochondrial FAO in Src activation and metastasis. Analysis of TCGA and other independent BC clinical data further reaffirmed the role of mitochondrial FAO and CPT genes in Src regulation and their significance in BC metastasis.

Original language	English (US)
Pages (from-to)	2154-2165
Number of pages	12
Journal	Cell Reports
Volume	14
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2016.02.004
State	Published - Mar 8 2016

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2016.02.004

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Park, J. H., Vithayathil, S., Kumar, S., Sung, P. L., Dobrolecki, L. E., Putluri, V., Bhat, V. B., Bhowmik, S. K., Gupta, V., Arora, K., Wu, D., Tsouko, E., Zhang, Y., Maity, S., Donti, T. R., Graham, B. H., Frigo, D. E., Coarfa, C., Yotnda, P., ... Kaipparettu, B. A. (2016). Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer. Cell Reports, 14(9), 2154-2165. https://doi.org/10.1016/j.celrep.2016.02.004

Park, JH, Vithayathil, S, Kumar, S, Sung, PL, Dobrolecki, LE, Putluri, V, Bhat, VB, Bhowmik, SK, Gupta, V, Arora, K, Wu, D, Tsouko, E, Zhang, Y, Maity, S, Donti, TR, Graham, BH, Frigo, DE, Coarfa, C, Yotnda, P, Putluri, N, Sreekumar, A, Lewis, MT, Creighton, CJ, Wong, LJC & Kaipparettu, BA 2016, 'Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer', Cell Reports, vol. 14, no. 9, pp. 2154-2165. https://doi.org/10.1016/j.celrep.2016.02.004

@article{c6d6b4ac23c241e8b1a8a2c09ce04fd4,

title = "Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer",

abstract = "Transmitochondrial cybrids and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in triple-negative breast cancer (TNBC). Analysis of cybrids and established breast cancer (BC) cell lines showed that metastatic TNBC maintains high levels of ATP through fatty acid β oxidation (FAO) and activates Src oncoprotein through autophosphorylation at Y419. Manipulation of FAO including the knocking down of carnitine palmitoyltransferase-1A (CPT1) and 2 (CPT2), the rate-limiting proteins of FAO, and analysis of patient-derived xenograft models confirmed the role of mitochondrial FAO in Src activation and metastasis. Analysis of TCGA and other independent BC clinical data further reaffirmed the role of mitochondrial FAO and CPT genes in Src regulation and their significance in BC metastasis.",

author = "Park, {Jun Hyoung} and Sajna Vithayathil and Santosh Kumar and Sung, {Pi Lin} and Dobrolecki, {Lacey Elizabeth} and Vasanta Putluri and Bhat, {Vadiraja B.} and Bhowmik, {Salil Kumar} and Vineet Gupta and Kavisha Arora and Danli Wu and Efrosini Tsouko and Yiqun Zhang and Suman Maity and Donti, {Taraka R.} and Graham, {Brett H.} and Frigo, {Daniel E.} and Cristian Coarfa and Patricia Yotnda and Nagireddy Putluri and Arun Sreekumar and Lewis, {Michael T.} and Creighton, {Chad J.} and Wong, {Lee Jun C} and Kaipparettu, {Benny Abraham}",

note = "Funding Information: Dr. Hostetler provided FA-BSA, Drs. Zhang and Insun supported animal experiments, and Mr. Sederstrom supported flow cytometry. Funding to B.A.K.: NIH (R21CA179720, R21CA173150, R21CA179720S1, R21CA179720S2, and U54-CA149196 Pilot Project), DOD (DAMD W81XWH-11-1-0292), and DLDCC Pilot Projects. Other support: BCM Cancer Center Grant (P30CA125123), DEF (NIH-R01CA184208), MTL (P50CA50183, R01CA112305, U54 CA149196, P01CA30195), AS (R21CA185516 and U01CA179674), NP (ACS 127430-RSG-15-105-01-CNE), CPRIT Proteomics and Metabolomics Core Facility (RP120092 and Mass spectrometry Center of Excellence by Agilent), and Cytometry and Cell Sorting Core (NIAID P30AI036211 and NCRR S10RR024574). Funding Information: Dr. Hostetler provided FA-BSA, Drs. Zhang and Insun supported animal experiments, and Mr. Sederstrom supported flow cytometry. Funding to B.A.K.: NIH (R21CA179720, R21CA173150, R21CA179720S1, R21CA179720S2, and U54-CA149196 Pilot Project), DOD (DAMD W81XWH-11-1-0292), and DLDCC Pilot Projects. Other support: BCM Cancer Center Grant (P30CA125123), DEF (NIH-R01CA184208), MTL (P50CA50183, R01CA112305, U54 CA149196, P01CA30195), AS (R21CA185516 and U01CA179674), NP (ACS 127430-RSG-15-105-01-CNE), CPRIT Proteomics and Metabolomics Core Facility (RP120092 and Mass spectrometry Center of Excellence by Agilent), and Cytometry and Cell Sorting Core (NIAID P30AI036211 and NCRR S10RR024574). Publisher Copyright: {\textcopyright} 2016 The Authors.",

year = "2016",

month = mar,

day = "8",

doi = "10.1016/j.celrep.2016.02.004",

language = "English (US)",

volume = "14",

pages = "2154--2165",

journal = "Cell Reports",

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TY - JOUR

T1 - Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer

AU - Park, Jun Hyoung

AU - Vithayathil, Sajna

AU - Kumar, Santosh

AU - Sung, Pi Lin

AU - Dobrolecki, Lacey Elizabeth

AU - Putluri, Vasanta

AU - Bhat, Vadiraja B.

AU - Bhowmik, Salil Kumar

AU - Gupta, Vineet

AU - Arora, Kavisha

AU - Wu, Danli

AU - Tsouko, Efrosini

AU - Zhang, Yiqun

AU - Maity, Suman

AU - Donti, Taraka R.

AU - Graham, Brett H.

AU - Frigo, Daniel E.

AU - Coarfa, Cristian

AU - Yotnda, Patricia

AU - Putluri, Nagireddy

AU - Sreekumar, Arun

AU - Lewis, Michael T.

AU - Creighton, Chad J.

AU - Wong, Lee Jun C

AU - Kaipparettu, Benny Abraham

N1 - Funding Information: Dr. Hostetler provided FA-BSA, Drs. Zhang and Insun supported animal experiments, and Mr. Sederstrom supported flow cytometry. Funding to B.A.K.: NIH (R21CA179720, R21CA173150, R21CA179720S1, R21CA179720S2, and U54-CA149196 Pilot Project), DOD (DAMD W81XWH-11-1-0292), and DLDCC Pilot Projects. Other support: BCM Cancer Center Grant (P30CA125123), DEF (NIH-R01CA184208), MTL (P50CA50183, R01CA112305, U54 CA149196, P01CA30195), AS (R21CA185516 and U01CA179674), NP (ACS 127430-RSG-15-105-01-CNE), CPRIT Proteomics and Metabolomics Core Facility (RP120092 and Mass spectrometry Center of Excellence by Agilent), and Cytometry and Cell Sorting Core (NIAID P30AI036211 and NCRR S10RR024574). Funding Information: Dr. Hostetler provided FA-BSA, Drs. Zhang and Insun supported animal experiments, and Mr. Sederstrom supported flow cytometry. Funding to B.A.K.: NIH (R21CA179720, R21CA173150, R21CA179720S1, R21CA179720S2, and U54-CA149196 Pilot Project), DOD (DAMD W81XWH-11-1-0292), and DLDCC Pilot Projects. Other support: BCM Cancer Center Grant (P30CA125123), DEF (NIH-R01CA184208), MTL (P50CA50183, R01CA112305, U54 CA149196, P01CA30195), AS (R21CA185516 and U01CA179674), NP (ACS 127430-RSG-15-105-01-CNE), CPRIT Proteomics and Metabolomics Core Facility (RP120092 and Mass spectrometry Center of Excellence by Agilent), and Cytometry and Cell Sorting Core (NIAID P30AI036211 and NCRR S10RR024574). Publisher Copyright: © 2016 The Authors.

PY - 2016/3/8

Y1 - 2016/3/8

N2 - Transmitochondrial cybrids and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in triple-negative breast cancer (TNBC). Analysis of cybrids and established breast cancer (BC) cell lines showed that metastatic TNBC maintains high levels of ATP through fatty acid β oxidation (FAO) and activates Src oncoprotein through autophosphorylation at Y419. Manipulation of FAO including the knocking down of carnitine palmitoyltransferase-1A (CPT1) and 2 (CPT2), the rate-limiting proteins of FAO, and analysis of patient-derived xenograft models confirmed the role of mitochondrial FAO in Src activation and metastasis. Analysis of TCGA and other independent BC clinical data further reaffirmed the role of mitochondrial FAO and CPT genes in Src regulation and their significance in BC metastasis.

AB - Transmitochondrial cybrids and multiple OMICs approaches were used to understand mitochondrial reprogramming and mitochondria-regulated cancer pathways in triple-negative breast cancer (TNBC). Analysis of cybrids and established breast cancer (BC) cell lines showed that metastatic TNBC maintains high levels of ATP through fatty acid β oxidation (FAO) and activates Src oncoprotein through autophosphorylation at Y419. Manipulation of FAO including the knocking down of carnitine palmitoyltransferase-1A (CPT1) and 2 (CPT2), the rate-limiting proteins of FAO, and analysis of patient-derived xenograft models confirmed the role of mitochondrial FAO in Src activation and metastasis. Analysis of TCGA and other independent BC clinical data further reaffirmed the role of mitochondrial FAO and CPT genes in Src regulation and their significance in BC metastasis.

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JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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ER -

Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer

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