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 language | English (US) |
|---|---|
| Journal | Cell Reports |
| DOIs | |
| State | Accepted/In press - Dec 29 2015 |
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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
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 journal › Article
}
TY - JOUR
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
PY - 2015/12/29
Y1 - 2015/12/29
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
UR - http://www.scopus.com/inward/record.url?scp=84979738962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979738962&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.07.009
DO - 10.1016/j.celrep.2016.07.009
M3 - Article
C2 - 27477280
AN - SCOPUS:84979738962
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
ER -