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28.08.2018 | Short Communication

Enhancing 5-fluorouracil efficacy through suppression of PKM2 in colorectal cancer cells

Zeitschrift:
Cancer Chemotherapy and Pharmacology
Autoren:
Yong Cao, Yan Lin, Dongxu Wang, Di Pan, Ying Zhang, Yu Jin, Changqing Zheng
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00280-018-3676-7) contains supplementary material, which is available to authorized users.

Abstract

Purpose

Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, the role of PKM2 in the anticancer efficacy of 5-fluorouracil (5-FU) was evaluated in colorectal cancer (CRC).

Methods

HCT116, SW480 and HT-29 cells were used by transfection with lentiviral vectors expressing short hairpin RNA (shRNA) against PKM2. In response to 5-FU treatment, cellular proliferation was examined, the levels of ATP/ADP ratio were monitored, the intracellular accumulation of 5-FU was measured, and intracellular levels of phosphoenolpyruvate (PEP), pyruvate and lactate were evaluated by using liquid chromatography–mass spectrometry (LC–MS). A CRC subcutaneous tumor model was performed to investigate the effect of PKM2 inhibition on 5-FU efficacy in vivo.

Results

Suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP/ADP ratio resulted in the intracellular accumulation of 5-FU, consequently enhancing the therapeutic efficacy of this drug in several CRC cell lines. Furthermore, the enhanced efficacy of 5-FU by simultaneous inhibition of PKM2 was demonstrated in an in vivo HCT116 CRC model.

Conclusion

We show that the combination treatment showed superior anticancer efficacy as compared to 5-FU alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with CRC.

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Zusatzmaterial
Supplementary material 1 (DOC 1610 KB)
280_2018_3676_MOESM1_ESM.doc
Literatur
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