RT Journal Article
T1 MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer.
A1 Shukla, Surendra K
A1 Purohit, Vinee
A1 Mehla, Kamiya
A1 Gunda, Venugopal
A1 Chaika, Nina V
A1 Vernucci, Enza
A1 King, Ryan J
A1 Abrego, Jaime
A1 Goode, Gennifer D
A1 Dasgupta, Aneesha
A1 Illies, Alysha L
A1 Gebregiworgis, Teklab
A1 Dai, Bingbing
A1 Augustine, Jithesh J
A1 Murthy, Divya
A1 Attri, Kuldeep S
A1 Mashadova, Oksana
A1 Grandgenett, Paul M
A1 Powers, Robert
A1 Ly, Quan P
A1 Lazenby, Audrey J
A1 Grem, Jean L
A1 Yu, Fang
A1 Matés, José M
A1 Asara, John M
A1 Kim, Jung-Whan
A1 Hankins, Jordan H
A1 Weekes, Colin
A1 Hollingsworth, Michael A
A1 Serkova, Natalie J
A1 Sasson, Aaron R
A1 Fleming, Jason B
A1 Oliveto, Jennifer M
A1 Lyssiotis, Costas A
A1 Cantley, Lewis C
A1 Berim, Lyudmyla
A1 Singh, Pankaj K
K1 HIF-1α
K1 MUC1
K1 cancer metabolism
K1 chemotherapy resistance
K1 gemcitabine
K1 mucin
K1 non-oxidative pentose phosphate pathway
K1 nucleotide synthesis
K1 pancreatic cancer
K1 pyrimidine biosynthesis
AB 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.
YR 2017
FD 2017
LK http://hdl.handle.net/10668/11393
UL http://hdl.handle.net/10668/11393
LA en
DS RISalud
RD Apr 6, 2025