Loss of SLC25A11 causes suppression of NSCLC and melanoma tumor formation

Jae Seon Lee, Ho Lee, Soohyun Lee, Joon Hee Kang, Seon Hyeong Lee, Seul Gi Kim, Eunae Sandra Cho, Nam Hee Kim, Jong In Yook, Soo Youl Kim

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22 Citations (Scopus)

Abstract

Background: Fast growing cancer cells require greater amounts of ATP than normal cells. Although glycolysis was suggested as a source of anabolic metabolism based on lactate production, the main source of ATP to support cancer cell metabolism remains unidentified. Methods: We have proposed that the oxoglutarate carrier SLC25A11 is important for ATP production in cancer by NADH transportation from the cytosol to mitochondria as a malate. We have examined not only changes of ATP and NADH but also changes of metabolites after SLC25A11 knock down in cancer cells. Findings: The mitochondrial electron transport chain was functionally active in cancer cells. The cytosolic to mitochondrial NADH ratio was higher in non-small cell lung cancer (NSCLC) and melanoma cells than in normal cells. This was consistent with higher levels of the oxoglutarate carrier SLC25A11. Blocking malate transport by knockdown of SLC25A11 significantly impaired ATP production and inhibited the growth of cancer cells, which was not observed in normal cells. In in vivo experiments, heterozygote of SLC25A11 knock out mice suppressed KRAS LA2 lung tumor formation by cross breeding. Interpretation: Cancer cells critically depended on the oxoglutarate carrier SLC25A11 for transporting NADH from cytosol to mitochondria as a malate form for the purpose of ATP production. Therefore blocking SLC25A11 may have an advantage in stopping cancer growth by reducing ATP production. Fund: The Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT to SYK (NRF-2017R1A2B2003428).

Original languageEnglish
Pages (from-to)184-197
Number of pages14
JournalEBioMedicine
Volume40
DOIs
Publication statusPublished - 2019 Feb

Bibliographical note

Funding Information:
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT to SYK ( NRF-2017R1A2B2003428 ) and by a research grant from the National Cancer Center in Korea to SYK; NCC1910291-1).

Funding Information:
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT to SYK (NRF-2017R1A2B2003428) and by a research grant from the National Cancer Center in Korea to SYK; NCC1910291-1).We thank Ms. Mi Ae Kim in the Microscopy Core and Mr. Tae Sik Kim in the Flow Cytometry Core (National Cancer Center, Korea) for their expert assistance and helpful suggestions.

Publisher Copyright:
© 2019 The Authors

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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