Serine deprivation enhances antineoplastic activity of biguanides.
Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin). Serine synthesis was not inhibited by biguanides. Instead, metabolic studies indicated a requirement for serine to allow cells to compensate for biguanide-induced decrease in oxidative phosphorylation by upregulating glycolysis. Furthermore, serine deprivation modified the impact of metformin on the relative abundance of metabolites within the citric acid cycle. In mice, a serine-deficient diet reduced serine levels in tumors and significantly enhanced the tumor growth-inhibitory actions of biguanide treatment. Our results define a dietary manipulation that can enhance the efficacy of biguanides as antineoplastic agents that target cancer cell energy metabolism.
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Simon-Pierre
SP
Gravel
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. Department of Oncology, McGill University, Montreal, Quebec, Canada. Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Laura
L
Hulea
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Nader
N
Toban
Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Elena
E
Birman
Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Marie-José
MJ
Blouin
Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Mahvash
M
Zakikhani
Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Yunhua
Y
Zhao
Department of Biochemistry, McGill University, Montreal, Quebec, Canada. Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. Department of Oncology, McGill University, Montreal, Quebec, Canada. Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada. michael.pollak@mcgill.ca julie.st-pierre@mcgill.ca ivan.topisirovic@mcgill.ca.
Ivan
I
Topisirovic
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. Department of Biochemistry, McGill University, Montreal, Quebec, Canada. michael.pollak@mcgill.ca julie.st-pierre@mcgill.ca ivan.topisirovic@mcgill.ca.
Julie
J
St-Pierre
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. Department of Oncology, McGill University, Montreal, Quebec, Canada. Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada. Division of Cancer Prevention, McGill University, Montreal, Quebec, Canada. michael.pollak@mcgill.ca julie.st-pierre@mcgill.ca ivan.topisirovic@mcgill.ca.
Michael
M
Pollak
D000818:Animals; D001645:Biguanides / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008687:Metformin; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010629:Phenformin / Q000008:administration & dosage*; D012694:Serine / Q000096:biosynthesis / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D001645:Biguanides; D012694:Serine; D008687:Metformin; D010629:Phenformin