title: Treatment with the MEK inhibitor U0126 induces decreased hyperpolarized pyruvate to lactate conversion in breast, but not prostate, cancer cells.
abstract: Alterations in cell metabolism are increasingly being recognized as a hallmark of cancer and are being exploited for the development of diagnostic tools and targeted therapeutics. Recently, ¹³C MRS-detectable hyperpolarized pyruvate to lactate conversion has been validated in models as a noninvasive imaging method for the detection of tumors and treatment response, and has successfully passed phase I clinical trials. To date, response to treatment has been associated with a decrease in hyperpolarized lactate production. In this study, we monitored the effect of treatment with the mitogen-activated protein kinase (MEK) inhibitor U0126 in prostate and breast cancer cells. Following treatment, we observed a 31% decrease in the flux of hyperpolarized ¹³C label in treated MCF-7 breast cancer cells relative to controls. In contrast, and unexpectedly, the flux increased to 167% in treated PC3 prostate cancer cells. To mechanistically explain these observations, we investigated treatment-induced changes in the different factors known to affect the pyruvate to lactate conversion. NADH (nicotinamide adenine dinucleotide, reduced form) levels remained unchanged, whereas lactate dehydrogenase expression and activity, as well as intracellular lactate, increased in both cell lines, providing an explanation for the elevated hyperpolarized lactate observed in PC3 cells. The expression of MCT1, which mediates pyruvate transport, decreased in treated MCF-7, but not PC3, cells. This identifies pyruvate transport as rate limiting in U0126-treated MCF-7 cells and explains the decrease in hyperpolarized lactate observed in these cells following treatment. Our findings highlight the complexity of interactions between MEK and metabolism, and the need for mechanistic validation before hyperpolarized ¹³C MRS can be used to monitor treatment-induced molecular responses.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94158-2512, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lodi
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Woods
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002070:Butadienes / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*
chemical_list: D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D019344:Lactic Acid; D019289:Pyruvic Acid; D020929:Mitogen-Activated Protein Kinase Kinases