Details

Autor(en) / Beteiligte

• Iwamoto, Hideki
• Abe, Mitsuhiko
• Yang, Yunlong
• Cui, Dongmei
• Seki, Takahiro
• Nakamura, Masaki
• Hosaka, Kayoko
• Lim, Sharon
• Wu, Jieyu
• He, Xingkang
• Sun, Xiaoting
• Lu, Yongtian
• Zhou, Qingjun
• Shi, Weiyun
• Torimura, Takuji
• Nie, Guohui
• Li, Qi
• Cao, Yihai

Titel

Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance

Ist Teil von

• Cell metabolism, 2018-07, Vol.28 (1), p.104-117.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• Intrinsic and evasive antiangiogenic drug (AAD) resistance is frequently developed in cancer patients, and molecular mechanisms underlying AAD resistance remain largely unknown. Here we describe AAD-triggered, lipid-dependent metabolic reprogramming as an alternative mechanism of AAD resistance. Unexpectedly, tumor angiogenesis in adipose and non-adipose environments is equally sensitive to AAD treatment. AAD-treated tumors in adipose environment show accelerated growth rates in the presence of a minimal number of microvessels. Mechanistically, AAD-induced tumor hypoxia initiates the fatty acid oxidation metabolic reprogramming and increases uptake of free fatty acid (FFA) that stimulates cancer cell proliferation. Inhibition of carnitine palmitoyl transferase 1A (CPT1) significantly compromises the FFA-induced cell proliferation. Genetic and pharmacological loss of CPT1 function sensitizes AAD therapeutic efficacy and enhances its anti-tumor effects. Together, we propose an effective cancer therapy concept by combining drugs that target angiogenesis and lipid metabolism. [Display omitted] •Tumors grown in adipose tissues tend to be AAD resistant•AAD induces hypoxia and limits glucose supply and induces lipolysis•Tumor cells switch from glycolysis to FAO metabolism upon AAD treatment•Dual targeting angiogenesis and FAO increases anti-tumor activity Antiangiogenic drug (AAD) resistance is a frequent problem in cancer patients. Iwamoto et al. show that vascularization is not a limiting factor. Instead, AAD triggered a lipid-dependent metabolic reprogramming, resulting in increased free fatty acid and cancer cell proliferation. Inhibition of fatty acid oxidation enhanced the therapeutic efficacy of AAD.