Malignant tumors, including colorectal cancer (CRC), usually rely on ATP generation through aerobic glycolysis for both rapid growth and chemotherapy resistance. The M2 isoform of pyruvate kinase (PKM2) has a key role in catalyzing glycolysis, and PKM2 expression varies even within a single tumor. In this study, we confirmed that expression of PKM2 is heterogeneous in CRC cells, namely high in oxaliplatin-resistant cells but relatively low in sensitive cells, and found that chemoresistant cells had enhanced glycolysis and ATP production. In addition, we report a PKM2-dependent mechanism through which chemosensitive cells may gradually transform into chemoresistant cells. The circular RNA hsa_circ_0005963 (termed ciRS-122 in this study), which was determined to be a sponge for the PKM2-targeting miR-122, was positively correlated with chemoresistance. In vitro and in vivo studies showed that exosomes from oxaliplatin-resistant cells delivered ciRS-122 to sensitive cells, thereby promoting glycolysis and drug resistance through miR-122 sponging and PKM2 upregulation. Moreover, si-ciRS-122 transported by exosomes could suppress glycolysis and reverse resistance to oxaliplatin by regulating the ciRS-122-miR-122-PKM2 pathway in vivo. Exosomes derived from chemoresistant CRC cells could transfer ciRS-122 across cells and promote glycolysis to reduce drug susceptibility in chemosensitive cells. This intercellular signal delivery suggests a potential novel therapeutic target and establishes a foundation for future clinical applications in drug-resistant CRC.
Keywords: PKM2; aerobic glycolysis; chemoresistance; circRNA; exosome; hsa_circ_0005963.
© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.