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 journalArticle

40 Citations (Scopus)

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. In Brief: Padanad et al. find that . ACSL3 is the critical enzyme required for viability of mutant . KRAS lung cancer cells in vitro and for lung cancer initiation and progression in vivo. . ACSL3 mediates survival and tumorigenesis of mutant . KRAS lung cancer cells by promoting uptake, retention, and β-oxidation of fatty acids.

Original languageEnglish (US)
JournalCell Reports
DOIs
StateAccepted/In press - Dec 29 2015

Fingerprint

Coenzyme A Ligases
Lung Neoplasms
Carcinogenesis
Fatty Acids
Cells
Oxidation
Lung
Acyl Coenzyme A
Metabolism
Lipids
Ligases
Esters
Adenosine Triphosphate
Metabolic Networks and Pathways
Oncogenes
Substrates
Enzymes
Cause of Death
Homeostasis
Survival

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)

Cite this

Padanad, M. S., Konstantinidou, G., Venkateswaran, N., Melegari, M., Rindhe, S., Mitsche, M., ... Scaglioni, P. P. (Accepted/In press). Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. Cell Reports. 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, 29.12.2015.

Research output: Contribution to journalArticle

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 2015, 'Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis', Cell Reports. 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. 2015.
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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. In Brief: Padanad et al. find that . ACSL3 is the critical enzyme required for viability of mutant . KRAS lung cancer cells in vitro and for lung cancer initiation and progression in vivo. . ACSL3 mediates survival and tumorigenesis of mutant . KRAS lung cancer cells by promoting uptake, retention, and β-oxidation of fatty acids.",
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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

PY - 2015/12/29

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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. In Brief: Padanad et al. find that . ACSL3 is the critical enzyme required for viability of mutant . KRAS lung cancer cells in vitro and for lung cancer initiation and progression in vivo. . ACSL3 mediates survival and tumorigenesis of mutant . KRAS lung cancer cells by promoting uptake, retention, and β-oxidation of fatty acids.

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. In Brief: Padanad et al. find that . ACSL3 is the critical enzyme required for viability of mutant . KRAS lung cancer cells in vitro and for lung cancer initiation and progression in vivo. . ACSL3 mediates survival and tumorigenesis of mutant . KRAS lung cancer cells by promoting uptake, retention, and β-oxidation of fatty acids.

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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