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.
[1]Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden.
[2]Kurume Univ, Sch Med, Dept Med, Div Gastroenterol, Kurume, Fukuoka, Japan.
[3]Fudan Univ, Sch Basic Med Sci, Dept Cellular & Genet Med, Shanghai 200032, Peoples R China.
[4]Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou, Guangdong, Peoples R China.
[5]Shenzhen Univ, Affiliated Hosp 1, Peoples Hosp Shenzhen 2, Key Lab Int Collaborat, Shenzhen 518035, Peoples R China.
[6]Shandong Acad Med Sci, Shandong Eye Inst, Shandong Prov Key Lab Ophthalmol, State Key Lab Cultivat Base, Yanerdao Rd, Qingdao 266071, Peoples R China.
[7]Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, Shanghai, Peoples R China.
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