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April 5th, 2025
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Korea Advanced Institute of Science and Technology (KAIST)
biochemistry
biorxiv

Linoleic acid metabolite, 13-S-hydroxyoctadecadienoic acid, suppresses cancer cell growth by inhibiting mTOR

Park, S. J.Open in Google Scholar•Kwon, H.Open in Google Scholar•Yang, A. Y.Open in Google Scholar•Lee, B.Open in Google Scholar•Lee, H.Open in Google Scholar•Park, S. E.Open in Google Scholar•Lee, S.Open in Google Scholar•Park, B. B.Open in Google Scholar•Kim, Y.Open in Google Scholar•Lee, J.Open in Google Scholaret al.

Mechanistic target of rapamycin (mTOR) is a key protein kinase that integrates various internal and external signals to control biological events including cell growth. Whereas substantial efforts were made to elucidate protein subunits interacting with mTOR, endogenous metabolite-mTOR interactions remain largely unknown. Using affinity protein purification and mass spectrometry, we identified direct binding of mTOR to 13-S-hydroxyoctadecadienoic acid (13-S-HODE) which is an oxygenated metabolite of linoleic acid, a polyunsaturated essential fatty acid. Interaction of 13-S-HODE with the catalytic ATP-binding domain of mTOR prevented its kinase activity in an ATP competitive manner. Furthermore, either 13-S-HODE treatment or expression of arachidonate 15-lipoxygenase (ALOX15), an enzyme responsible for 13-S-HODE production, reduced mTOR signaling, thereby suppressing the growth of cancer cells as well as tumor xenografts. Our results highlight the importance of 13-S-HODE serving as a tumor suppressive, mTOR-inhibiting metabolite that links polyunsaturated fatty acid metabolism and the mTOR signaling in controlling cancer cell growth.

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