Cancer Lipid Metabolism Confers Antiangiogenic Drug Resistance

Publication date: Available online 31 May 2018
Source:Cell Metabolism
Author(s): Hideki Iwamoto, Mitsuhiko Abe, Yunlong Yang, Dongmei Cui, Takahiro Seki, Masaki Nakamura, Kayoko Hosaka, Sharon Lim, Jieyu Wu, Xingkang He, Xiaoting Sun, Yongtian Lu, Qingjun Zhou, Weiyun Shi, Takuji Torimura, Guohui Nie, Qi Li, Yihai Cao
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.

Graphical abstract

Teaser

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.


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