Altered glutamine metabolism in platinum resistant ovarian cancer
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Chantelle D. Hudson1, Alyssa Savadelis1, Anil Belur Nagaraj2, Peronne Joseph2, Stefanie Avril3, Analisa DiFeo2,*, Norbert Avril1,*
1Department of Radiology, Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
3Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
*Shared senior authors
Norbert Avril, email: Norbert.Avril@Case.edu
Keywords: ovarian cancer, cisplatin resistance, glutamine metabolism, glutaminase inhibitors
Received: February 13, 2016 Accepted: April 10, 2016 Published: May 12, 2016
Ovarian cancer is characterized by an increase in cellular energy metabolism, which is predominantly satisfied by glucose and glutamine. Targeting metabolic pathways is an attractive approach to enhance the therapeutic effectiveness and to potentially overcome drug resistance in ovarian cancer. In platinum-sensitive ovarian cancer cell lines the metabolism of both, glucose and glutamine was initially up-regulated in response to platinum treatment. In contrast, platinum-resistant cells revealed a significant dependency on the presence of glutamine, with an upregulated expression of glutamine transporter ASCT2 and glutaminase. This resulted in a higher oxygen consumption rate compared to platinum-sensitive cell lines reflecting the increased dependency of glutamine utilization through the tricarboxylic acid cycle. The important role of glutamine metabolism was confirmed by stable overexpression of glutaminase, which conferred platinum resistance. Conversely, shRNA knockdown of glutaminase in platinum resistant cells resulted in re-sensitization to platinum treatment. Importantly, combining the glutaminase inhibitor BPTES with platinum synergistically inhibited platinum sensitive and resistant ovarian cancers in vitro. Apoptotic induction was significantly increased using platinum together with BPTES compared to either treatment alone. Our findings suggest that targeting glutamine metabolism together with platinum based chemotherapy offers a potential treatment strategy particularly in drug resistant ovarian cancer.
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