Hyperpolarized 13C spectroscopic imaging informs on hypoxia-inducible factor-1 and myc activity downstream of platelet-derived growth factor receptor.
The recent development of hyperpolarized (13)C magnetic resonance spectroscopic imaging provides a novel method for in vivo metabolic imaging with potential applications for detection of cancer and response to treatment. Chemotherapy-induced apoptosis was shown to decrease the flux of hyperpolarized (13)C label from pyruvate to lactate due to depletion of NADH, the coenzyme of lactate dehydrogenase. In contrast, we show here that in PC-3MM2 tumors, inhibition of platelet-derived growth factor receptor with imatinib reduces the conversion of hyperpolarized pyruvate to lactate by lowering the expression of lactate dehydrogenase itself. This was accompanied by reduced expression of vascular endothelial growth factor and glutaminase, and is likely mediated by reduced expression of their transcriptional factors hypoxia-inducible factor-1 and c-Myc. Our results indicate that hyperpolarized (13)C MRSI could potentially detect the molecular effect of various cell signaling inhibitors, thus providing a radiation-free method to predict tumor response.
Dafni
Hagit
H
Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California 94158, USA. hagit.dafni@weizmann.ac.il
Larson
Peder E Z
PE
Hu
Simon
S
Yoshihara
Hikari A I
HA
Ward
Christopher S
CS
Venkatesh
Humsa S
HS
Wang
Chunsheng
C
Zhang
Xiaoliang
X
Vigneron
Daniel B
DB
Ronen
Sabrina M
SM
D000818:Animals; D001549:Benzamides; D002199:Capillary Permeability / Q000187:drug effects; D002247:Carbon Isotopes; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D000068877:Imatinib Mesylate; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D001549:Benzamides; D002247:Carbon Isotopes; D051793:Hypoxia-Inducible Factor 1; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D019344:Lactic Acid; D000068877:Imatinib Mesylate; D007770:L-Lactate Dehydrogenase; D017479:Receptors, Platelet-Derived Growth Factor; D017239:Paclitaxel