MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer.,Cancer Cell

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MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer.
Cancer Cell ( IF 48.8 ) Pub Date : 2017-07-10 , DOI: 10.1016/j.ccell.2017.06.004
Surendra K Shukla ₁ , Vinee Purohit ₂ , Kamiya Mehla ₁ , Venugopal Gunda ₁ , Nina V Chaika ₁ , Enza Vernucci ₁ , Ryan J King ₁ , Jaime Abrego ₁ , Gennifer D Goode ₁ , Aneesha Dasgupta ₁ , Alysha L Illies ₁ , Teklab Gebregiworgis ₃ , Bingbing Dai ₄ , Jithesh J Augustine ₄ , Divya Murthy ₁ , Kuldeep S Attri ₁ , Oksana Mashadova ₅ , Paul M Grandgenett ₁ , Robert Powers ₃ , Quan P Ly ₆ , Audrey J Lazenby ₇ , Jean L Grem ₈ , Fang Yu ₉ , José M Matés ₁₀ , John M Asara ₁₁ , Jung-Whan Kim ₁₂ , Jordan H Hankins ₁₃ , Colin Weekes ₁₄ , Michael A Hollingsworth ₁ , Natalie J Serkova ₁₅ , Aaron R Sasson ₁₆ , Jason B Fleming ₄ , Jennifer M Oliveto ₁₃ , Costas A Lyssiotis ₁₇ , Lewis C Cantley ₅ , Lyudmyla Berim ₈ , Pankaj K Singh ₂

Affiliation

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Molecular Biology and Biochemistry, University of Málaga and IBIMA, 29071 Málaga, Spain.
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Department of Biological Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, USA.
Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045, USA.
Department of Surgery, Health Sciences Center T18-065, Stony Brook Medicine, Stony Brook, NY 11794, USA.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48103, USA.

Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.

中文翻译：

MUC1 和 HIF-1alpha 信号串扰诱导合成代谢葡萄糖代谢，从而赋予吉西他滨对胰腺癌的耐药性。

由于耐药性而导致的癌症治疗反应不佳仍然是一个临床挑战。本研究建立了胰腺癌中广泛流行的吉西他滨耐药机制，即糖酵解通量增加导致癌细胞中的葡萄糖成瘾，并相应增加嘧啶生物合成，从而提高脱氧胞苷三磷酸（dCTP）的内在水平。 dCTP 水平升高会通过分子竞争降低吉西他滨的有效水平。我们还证明，MUC1 调节的缺氧诱导因子 1α (HIF-1α) 的稳定性介导了这种代谢重编程。靶向 HIF-1α 或从头嘧啶生物合成，与吉西他滨联合，可显着减轻肿瘤负荷。最后，TKT 和 CTPS 的表达减少（调节嘧啶生物合成的通量）与使用氟嘧啶类似物的胰腺癌患者更好的预后相关。

更新日期：2017-07-11

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