Insights into gemcitabine resistance and the potential for therapeutic monitoring
- 172 Downloads
Gemcitabine is an important component of pancreatic cancer clinical management. Unfortunately, acquired gemcitabine resistance is widespread and there are limitations to predicting and monitoring therapeutic outcomes.
To investigate the potential of metabolomics to differentiate pancreatic cancer cells that develops resistance or respond to gemcitabine treatment.
We applied 1D 1H and 2D 1H–13C HSQC NMR methods to profile the metabolic signature of pancreatic cancer cells. 13C6-glucose labeling identified 30 key metabolites uniquely altered between wild-type and gemcitabine-resistant cells upon gemcitabine treatment. Gemcitabine resistance was observed to reprogram glucose metabolism and to enhance the pyrimidine synthesis pathway. Myo-inositol, taurine, glycerophosphocholine and creatinine phosphate exhibited a “binary switch” in response to gemcitabine treatment and acquired resistance.
Metabolic differences between naïve and resistant pancreatic cancer cells and, accordingly, their unique responses to gemcitabine treatment were revealed, which may be useful in the clinical setting for monitoring a patient’s therapeutic response.
KeywordsNMR metabolomics Pancreatic cancer Gemcitabine Drug resistance
This work was supported in part by funding from the National Institutes of Health Grant No. (R01 CA163649, NCI) to P.K.S. and R.P.; the Redox Biology Center (Grant No. P30 GM103335, NIGMS) to R.P.; the Nebraska Center for Integrated Biomolecular Communication (Grant No. P20 GM113126, NIGMS) to R.P.; American Association for Cancer Research (AACR)-Pancreatic Cancer Action Network (PanCAN) Career Development Award (Grant No. 30-20-25-SING) to P.K.S.; the Specialized Programs for Research Excellence (Grant No. SPORE, 2P50 CA127297, NCI) to P.K.S.; Pancreatic Tumor Microenvironment Research Network (Grant No. U54, CA163120, NCI) to P.K.S.; and Fred & Pamela Buffett Cancer Center Support Grant (Grant No. P30CA036727) to P.K.S. and R.P. The research was performed in facilities renovated with support from the National Institutes of Health (Grant No. RR015468-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors have no conflict of interest to declare.
This article does not contain any studies with human participants or animals performed by any of the authors.
- Chaika, N. V., Gebregiworgis, T., Lewallen, M. E., Purohit, V., Radhakrishnan, P., Liu, X., et al. (2012). MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 109(34), 13787–13792. https://doi.org/10.1073/pnas.1203339109.CrossRefPubMedPubMedCentralGoogle Scholar
- Gardner, S. G., Somerville, G. A., Marshall, D. D., Powers, R., Daum, R. S., Daum, R. S., et al. (2018). Metabolic mitigation of Staphylococcus aureus vancomycin intermediate-level susceptibility. Antimicrobial Agents and Chemotherapy. 62(1), e01608–e01617.Google Scholar
- Gaupp, R., Lei, S., Reed, J. M., Peisker, H., Boyle-Vavra, S., Bayer, A. S., et al. (2015). Staphylococcus aureus metabolic adaptations during the transition from a daptomycin susceptibility phenotype to a daptomycin nonsusceptibility phenotype. Antimicrobial Agents and Chemotherapy, 59(7), 4226–4238. https://doi.org/10.1128/aac.00160-15.CrossRefPubMedPubMedCentralGoogle Scholar
- Gebregiworgis, T., Purohit, V., Shukla, S. K., Tadros, S., Chaika, N. V., Abrego, J., et al. (2017). Glucose limitation alters glutamine metabolism in MUC1-overexpressing pancreatic cancer cells. Journal of Proteome Research, 16(10), 3536–3546. https://doi.org/10.1021/acs.jproteome.7b00246.CrossRefPubMedPubMedCentralGoogle Scholar
- Ju, H. Q., Gocho, T., Aguilar, M., Wu, M., Zhuang, Z. N., Fu, J., et al. (2015). Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. Molecular Cancer Therapeutics, 14(3), 788–798. https://doi.org/10.1158/1535-7163.MCT-14-0420.CrossRefPubMedGoogle Scholar
- Raykov, Z., Grekova, S. P., Bour, G., Lehn, J. M., Giese, N. A., Nicolau, C., et al. (2014). Myo-inositol trispyrophosphate-mediated hypoxia reversion controls pancreatic cancer in rodents and enhances gemcitabine efficacy. International Journal of Cancer, 134(11), 2572–2582. https://doi.org/10.1002/ijc.28597.CrossRefPubMedGoogle Scholar
- Shukla, S. K., Purohit, V., Mehla, K., Gunda, V., Chaika, N. V., Vernucci, E., et al. (2017). MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell, 32(1), 71–87. https://doi.org/10.1016/j.ccell.2017.06.004. (e77)CrossRefPubMedPubMedCentralGoogle Scholar
- Tu, S., Zhang, X., Luo, D., Liu, Z., Yang, X., Wan, H., et al. (2015). Effect of taurine on the proliferation and apoptosis of human hepatocellular carcinoma HepG2 cells. Experimental and Therapeutic Medicine, 10(1), 193–200. https://doi.org/10.3892/etm.2015.2476.CrossRefPubMedPubMedCentralGoogle Scholar