Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis

Mahesh S. Padanad; Georgia Konstantinidou; Niranjan Venkateswaran; Margherita Melegari; Smita Rindhe; Matthew Mitsche; Chendong Yang; Kimberly Batten; Kenneth E. Huffman; Jingwen Liu; Ximing Tang; Jaime Rodriguez-Canales; Neda Kalhor; Jerry W. Shay; John D. Minna; Jeffrey McDonald; Ignacio I. Wistuba; Ralph J. DeBerardinis; Pier Paolo Scaglioni

doi:10.1016/j.celrep.2016.07.009

Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis

Mahesh S. Padanad, Georgia Konstantinidou, Niranjan Venkateswaran, Margherita Melegari, Smita Rindhe, Matthew Mitsche, Chendong Yang, Kimberly Batten, Kenneth E. Huffman, Jingwen Liu, Ximing Tang, Jaime Rodriguez-Canales, Neda Kalhor, Jerry W. Shay, John D. Minna, Jeffrey McDonald, Ignacio I. Wistuba, Ralph J. DeBerardinis, Pier Paolo Scaglioni

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

Abstract

KRAS is one of the most commonly mutated oncogenes in human cancer. Mutant KRAS aberrantly regulates metabolic networks. However, the contribution of cellular metabolism to mutant KRAS tumorigenesis is not completely understood. We report that mutant KRAS regulates intracellular fatty acid metabolism through Acyl-coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3), which converts fatty acids into fatty Acyl-CoA esters, the substrates for lipid synthesis and β-oxidation. ACSL3 suppression is associated with depletion of cellular ATP and causes the death of lung cancer cells. Furthermore, mutant KRAS promotes the cellular uptake, retention, accumulation, and β-oxidation of fatty acids in lung cancer cells in an ACSL3-dependent manner. Finally, ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer. Our data demonstrate that mutant KRAS reprograms lipid homeostasis, establishing a metabolic requirement that could be exploited for therapeutic gain.

Original language	English (US)
Pages (from-to)	1614-1628
Number of pages	15
Journal	Cell Reports
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2016.07.009
State	Published - Aug 9 2016

Keywords

ACSL3
cancer metabolism
fatty acid oxidation
lipid metabolism
lung cancer
mouse cancer models
mutant KRAS

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Padanad, M. S., Konstantinidou, G., Venkateswaran, N., Melegari, M., Rindhe, S., Mitsche, M., Yang, C., Batten, K., Huffman, K. E., Liu, J., Tang, X., Rodriguez-Canales, J., Kalhor, N., Shay, J. W., Minna, J. D., McDonald, J., Wistuba, I. I., DeBerardinis, R. J., & Scaglioni, P. P. (2016). Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. Cell Reports, 16(6), 1614-1628. https://doi.org/10.1016/j.celrep.2016.07.009

Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. / Padanad, Mahesh S.; Konstantinidou, Georgia; Venkateswaran, Niranjan; Melegari, Margherita; Rindhe, Smita; Mitsche, Matthew; Yang, Chendong; Batten, Kimberly; Huffman, Kenneth E.; Liu, Jingwen; Tang, Ximing; Rodriguez-Canales, Jaime; Kalhor, Neda; Shay, Jerry W.; Minna, John D.; McDonald, Jeffrey; Wistuba, Ignacio I.; DeBerardinis, Ralph J.; Scaglioni, Pier Paolo.

In: Cell Reports, Vol. 16, No. 6, 09.08.2016, p. 1614-1628.

Research output: Contribution to journal › Article › peer-review

Padanad, MS, Konstantinidou, G, Venkateswaran, N, Melegari, M, Rindhe, S, Mitsche, M, Yang, C, Batten, K, Huffman, KE, Liu, J, Tang, X, Rodriguez-Canales, J, Kalhor, N, Shay, JW , Minna, JD , McDonald, J, Wistuba, II, DeBerardinis, RJ & Scaglioni, PP 2016, 'Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis', Cell Reports, vol. 16, no. 6, pp. 1614-1628. https://doi.org/10.1016/j.celrep.2016.07.009

Padanad, Mahesh S. ; Konstantinidou, Georgia ; Venkateswaran, Niranjan ; Melegari, Margherita ; Rindhe, Smita ; Mitsche, Matthew ; Yang, Chendong ; Batten, Kimberly ; Huffman, Kenneth E. ; Liu, Jingwen ; Tang, Ximing ; Rodriguez-Canales, Jaime ; Kalhor, Neda ; Shay, Jerry W. ; Minna, John D. ; McDonald, Jeffrey ; Wistuba, Ignacio I. ; DeBerardinis, Ralph J. ; Scaglioni, Pier Paolo. / Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. In: Cell Reports. 2016 ; Vol. 16, No. 6. pp. 1614-1628.

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title = "Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis",

abstract = "KRAS is one of the most commonly mutated oncogenes in human cancer. Mutant KRAS aberrantly regulates metabolic networks. However, the contribution of cellular metabolism to mutant KRAS tumorigenesis is not completely understood. We report that mutant KRAS regulates intracellular fatty acid metabolism through Acyl-coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3), which converts fatty acids into fatty Acyl-CoA esters, the substrates for lipid synthesis and β-oxidation. ACSL3 suppression is associated with depletion of cellular ATP and causes the death of lung cancer cells. Furthermore, mutant KRAS promotes the cellular uptake, retention, accumulation, and β-oxidation of fatty acids in lung cancer cells in an ACSL3-dependent manner. Finally, ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer. Our data demonstrate that mutant KRAS reprograms lipid homeostasis, establishing a metabolic requirement that could be exploited for therapeutic gain.",

keywords = "ACSL3, cancer metabolism, fatty acid oxidation, lipid metabolism, lung cancer, mouse cancer models, mutant KRAS",

author = "Padanad, {Mahesh S.} and Georgia Konstantinidou and Niranjan Venkateswaran and Margherita Melegari and Smita Rindhe and Matthew Mitsche and Chendong Yang and Kimberly Batten and Huffman, {Kenneth E.} and Jingwen Liu and Ximing Tang and Jaime Rodriguez-Canales and Neda Kalhor and Shay, {Jerry W.} and Minna, {John D.} and Jeffrey McDonald and Wistuba, {Ignacio I.} and DeBerardinis, {Ralph J.} and Scaglioni, {Pier Paolo}",

note = "Funding Information: We thank Dr. Harold E. Varmus for providing CCSP-rtTA/Tet-op-Kras mice and BK cells and Dr. Luc Girard and Dr. Helen Hobbs (University of Texas Southwestern Medical Center) for sharing bioinformatics data and expertise in lipid analysis, respectively. We also thank Dr. Andrea Rabellino and Dr. Edward Motea for assistance with transactivation assays and flow cytometer, respectively. The following financial support is acknowledged: American Cancer Society Scholar Award 13-068-01-TBG, CDMRP LCRP grant LC110229, CPRIT RP140672, NCI 5P50 CA70907-15, UT Southwestern Friends of the Comprehensive Cancer Center, the Gibson Foundation, and Texas 4000 (to P.P.S.); CPRIT RP140110 (to M.S.P.); CPRIT RP101496 (to G.K.); NCI R01 CA157996-01 and Welch Foundation research grant I-1733 (to R.J.D.); Lung Cancer SPORE (P50CA70907; to J.D.M., P.P.S., J.W.S., K.E.H., and I.I.W.); CPRIT RP120732 and RP110709 (to J.D.M. and K.E.H.); NIH K01GM109317 (to M. Mitsche); and 1P30 CA 142543-01, the Harold C. Simmons Comprehensive Cancer Center through NCI Cancer Center support grant and 2P30CA016672, MD Anderson{\textquoteright}s Institutional Tissue Bank, and NIH National Cancer Institute (to I.I.W.). ",

year = "2016",

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doi = "10.1016/j.celrep.2016.07.009",

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T1 - Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis

AU - Padanad, Mahesh S.

AU - Konstantinidou, Georgia

AU - Venkateswaran, Niranjan

AU - Melegari, Margherita

AU - Rindhe, Smita

AU - Mitsche, Matthew

AU - Yang, Chendong

AU - Batten, Kimberly

AU - Huffman, Kenneth E.

AU - Liu, Jingwen

AU - Tang, Ximing

AU - Rodriguez-Canales, Jaime

AU - Kalhor, Neda

AU - Shay, Jerry W.

AU - Minna, John D.

AU - McDonald, Jeffrey

AU - Wistuba, Ignacio I.

AU - DeBerardinis, Ralph J.

AU - Scaglioni, Pier Paolo

N1 - Funding Information: We thank Dr. Harold E. Varmus for providing CCSP-rtTA/Tet-op-Kras mice and BK cells and Dr. Luc Girard and Dr. Helen Hobbs (University of Texas Southwestern Medical Center) for sharing bioinformatics data and expertise in lipid analysis, respectively. We also thank Dr. Andrea Rabellino and Dr. Edward Motea for assistance with transactivation assays and flow cytometer, respectively. The following financial support is acknowledged: American Cancer Society Scholar Award 13-068-01-TBG, CDMRP LCRP grant LC110229, CPRIT RP140672, NCI 5P50 CA70907-15, UT Southwestern Friends of the Comprehensive Cancer Center, the Gibson Foundation, and Texas 4000 (to P.P.S.); CPRIT RP140110 (to M.S.P.); CPRIT RP101496 (to G.K.); NCI R01 CA157996-01 and Welch Foundation research grant I-1733 (to R.J.D.); Lung Cancer SPORE (P50CA70907; to J.D.M., P.P.S., J.W.S., K.E.H., and I.I.W.); CPRIT RP120732 and RP110709 (to J.D.M. and K.E.H.); NIH K01GM109317 (to M. Mitsche); and 1P30 CA 142543-01, the Harold C. Simmons Comprehensive Cancer Center through NCI Cancer Center support grant and 2P30CA016672, MD Anderson’s Institutional Tissue Bank, and NIH National Cancer Institute (to I.I.W.).

PY - 2016/8/9

Y1 - 2016/8/9

N2 - KRAS is one of the most commonly mutated oncogenes in human cancer. Mutant KRAS aberrantly regulates metabolic networks. However, the contribution of cellular metabolism to mutant KRAS tumorigenesis is not completely understood. We report that mutant KRAS regulates intracellular fatty acid metabolism through Acyl-coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3), which converts fatty acids into fatty Acyl-CoA esters, the substrates for lipid synthesis and β-oxidation. ACSL3 suppression is associated with depletion of cellular ATP and causes the death of lung cancer cells. Furthermore, mutant KRAS promotes the cellular uptake, retention, accumulation, and β-oxidation of fatty acids in lung cancer cells in an ACSL3-dependent manner. Finally, ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer. Our data demonstrate that mutant KRAS reprograms lipid homeostasis, establishing a metabolic requirement that could be exploited for therapeutic gain.

AB - KRAS is one of the most commonly mutated oncogenes in human cancer. Mutant KRAS aberrantly regulates metabolic networks. However, the contribution of cellular metabolism to mutant KRAS tumorigenesis is not completely understood. We report that mutant KRAS regulates intracellular fatty acid metabolism through Acyl-coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3), which converts fatty acids into fatty Acyl-CoA esters, the substrates for lipid synthesis and β-oxidation. ACSL3 suppression is associated with depletion of cellular ATP and causes the death of lung cancer cells. Furthermore, mutant KRAS promotes the cellular uptake, retention, accumulation, and β-oxidation of fatty acids in lung cancer cells in an ACSL3-dependent manner. Finally, ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer. Our data demonstrate that mutant KRAS reprograms lipid homeostasis, establishing a metabolic requirement that could be exploited for therapeutic gain.

KW - ACSL3

KW - cancer metabolism

KW - fatty acid oxidation

KW - lipid metabolism

KW - lung cancer

KW - mouse cancer models

KW - mutant KRAS

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JF - Cell Reports

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