TY - JOUR
T1 - Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer
AU - Watt, Matthew J.
AU - Clark, Ashlee K.
AU - Selth, Luke A.
AU - Haynes, Vanessa R.
AU - Lister, Natalie
AU - Rebello, Richard
AU - Porter, Laura H.
AU - Niranjan, Birunthi
AU - Whitby, Sarah T.
AU - Lo, Jennifer
AU - Huang, Cheng
AU - Schittenhelm, Ralf B.
AU - Anderson, Kimberley E.
AU - Furic, Luc
AU - Wijayaratne, Poornima R.
AU - Matzaris, Maria
AU - Montgomery, Magdalene K.
AU - Papargiris, Melissa
AU - Norden, Sam
AU - Febbraio, Maria
AU - Risbridger, Gail P.
AU - Frydenberg, Mark
AU - Nomura, Daniel K.
AU - Taylor, Renea A.
PY - 2019/2/6
Y1 - 2019/2/6
N2 - Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten −/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.
AB - Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten −/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.
KW - Prostate cancer
KW - cancer metabolism
KW - fatty acid translocase CD36
KW - treating prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85061159693&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1143224
UR - http://purl.org/au-research/grants/NHMRC/1102752
UR - http://purl.org/au-research/grants/NHMRC/1121057
UR - http://purl.org/au-research/grants/NHMRC/1077703
U2 - 10.1126/scitranslmed.aau5758
DO - 10.1126/scitranslmed.aau5758
M3 - Article
C2 - 30728288
AN - SCOPUS:85061159693
SN - 1946-6234
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 478
M1 - eaau5758
ER -
