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Cellular and Molecular Biology

Abstract #LB-186: c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism

Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang, Yun-Sil Lee, Kayoko Kita, Takafumi Ochi, Karen Zeller, Angelo De Marzo, Jennifer Van Eyk, Joshua Mendell and Chi Dang
Ping Gao
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Irina Tchernyshyov
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Tsung-Cheng Chang
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Yun-Sil Lee
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Kayoko Kita
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Takafumi Ochi
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Karen Zeller
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Angelo De Marzo
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Jennifer Van Eyk
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Joshua Mendell
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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Chi Dang
Johns Hopkins University School of Medicine, Baltimore, MD; Teikyo University, Sagamiko, Kanagawa ,, Japan
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DOI:  Published May 2009
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AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Abstract

Notwithstanding the renewed interest in the Warburg effect, which describes the propensity for cancer cells to avidly metabolize glucose to lactate, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine is a major source for energy, carbon and nitrogen for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood. Here, we report that the c-Myc oncogenic transcription factor regulates glutamine metabolism by a previously unsuspected mechanism which involves c-Myc suppression of miR-23 microRNAs that target and inhibit mitochondrial glutaminase, or GLS, the first enzyme that catabolizes glutamine. c-Myc also transactivates expression of glutamine transporter genes. We studied the human P-493 B cells that bear a tetracycline-repressible c-Myc construct, such that tetracycline withdrawal induces c-Myc and mitochondrial biogenesis followed by cell proliferation. We found through analyzing the mitochondrial proteome that GLS was increased dramatically in response to c-Myc induction. siRNA targeting GLS1 diminishes cell proliferation and increased apoptosis, indicating that GLS1 is necessary for Myc induced cell proliferation. GLS converts glutamine to glutamate that is further catabolized through the TCA cycle for the production of ATP or serves as substrate for glutathione synthesis. In this regard, depletion of glutamine significantly diminished proliferation of P-493 cell and the human prostate PC3 cancer cell line. Although GLS protein levels are induced >10-fold by c-Myc in P-493 cells, GLS1 mRNA did not vary significantly, suggesting that regulation of GLS protein levels by c-Myc is post-transcriptional. We document that c-Myc transcriptionally represses miR-23, which can inhibit the expression of GLS protein through targeting the 3\#8217;UTR. In addition to the responses of wild-type and miR-23 seed sequence mutant luciferase-GLS1-3\#8217;UTR reporter constructs, antisense miR-23 LNA oligonucleotides were able to elevate GLS protein levels in low c-Myc expressing P493 and PC3 cells, indicating that GLS1 mRNA is a target of miR-23 that inhibits glutaminase translation. Since miR-23 expression is decreased in human prostate cancer, we immunoblotted and found a correlation between c-Myc and GLS protein levels in human prostate cancer samples as compared with lowered expression in the corresponding normal prostate tissues. The unique means by which Myc regulates GLS uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species (ROS) homeostasis and provides a regulatory mechanism involving c-Myc and miRNAs for elevated expression of glutaminase and glutamine metabolism in human cancers.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-186.

Footnotes

  • 100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

  • American Association for Cancer Research
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Cancer Research: 69 (9 Supplement)
May 2009
Volume 69, Issue 9 Supplement
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Abstract #LB-186: c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism
Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang, Yun-Sil Lee, Kayoko Kita, Takafumi Ochi, Karen Zeller, Angelo De Marzo, Jennifer Van Eyk, Joshua Mendell and Chi Dang
Cancer Res May 1 2009 (69) (9 Supplement) LB-186;

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Abstract #LB-186: c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism
Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang, Yun-Sil Lee, Kayoko Kita, Takafumi Ochi, Karen Zeller, Angelo De Marzo, Jennifer Van Eyk, Joshua Mendell and Chi Dang
Cancer Res May 1 2009 (69) (9 Supplement) LB-186;
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