Knockdown of PKM2 and GLS1 expression can significantly reverse oxaliplatin-resistance in colorectal cancer cells

Abstract

Clinical treatment for colorectal cancer (CRC) thus far encounters a huge challenge due to oxaliplatin-resistance. As crucial rate-limiting enzymes in aerobic glycolysis and glutaminolysis, pyruvate kinase M2 type (PKM2) and kidney-type glutaminase (GLS1) are proposed to carry important implications in colorectal carcinogenesis and drug-resistance. This study aimed to explore the possible association of oxaliplatin-resistance with aerobic glycolysis/glutaminolysis indexed by PKM2/GLS1 expression. PKM2 and GLS1 expression was quantified by polymerase chain reaction (PCR) and Western blot techniques in CRC cell lines. The abilities of cell formation, kinetics, migration, invasion, survival and apoptosis, as well as permeability glycoprotein (Pgp) expression were inspected before and after knocking-down PKM2/GLS1 expression. In addition, the influence of knocking-down PKM2/GLS1 expression was evaluated in vivo. Differentiated PKM2 and GLS1 expression in both THC8307 and THC8307/Oxa cell lines was identified. In the THC8307 cell line, PKM2 and GLS1 can accelerate malignant behaviors, increase oxaliplatin-resistance, upregulate Pgp expression, and inhibit cell apoptosis. Contrastingly in the THC8307/Oxa cell line, knockdown of PKM2/GLS1 expression can restrain malignant behaviors, reestablish oxaliplatin-sensitivity, downregulate Pgp expression, and induce cell apoptosis. In xenograft, knockdown of PKM2/GLS1 expression can significantly inhibit tumor growth, reduce Pgp expression, and increase tumor apoptosis. Taken together, the present findings enriched our knowledge by demonstrating a significant association of PKM2 and GLS1 with oxaliplatin-resistance in CRC. We further propose that knockdown of PKM2/GLS1 expression may constitute a novel therapeutic strategy toward effective treatment for CRC.

Correlation of PKM2 and CD44 Protein Expression with Poor Prognosis in Platinum-Treated Epithelial Ovarian Cancer: A Retrospective Study

“…Indeed, there are several in vitro studies that demonstrate the interference of aerobic glycolysis and of PKM2 on platinum-sensitivity by modification of oxidative phosphorylation rate, by alteration of lactate production, and by restriction of drug oxidative role. For instance, knockdown of PKM2 expression in colorectal and bladder cancer cells re-boost platinum sensitivity and induce cell apoptosis [33,34]. Another recent study performed in ovarian cancer cell lines showed the overexpression of PKM2 that in turn increased CCND1 expression, whereas it decreased CDKN1A expression; determinants involved in the increase of proliferation and in the decrease of apoptosis of ovarian cancer cells [35].…”

PAK2–c-Myc–PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect

“…Considering the fact that the PKM2 overexpression is associated with chemoresistance in various cancers 59 , 60 , the PAK2–c-Myc–PKM2 axis might be responsible for chemoresistance in HNC. Interestingly, we observed that PAK2 depletion reduced chemotherapeutic resistance in HNC cells, which further correlates with poor survival of HNC patients with higher expression of PAK2.…”

Protein kinase function of pyruvate kinase M2 and cancer

“…miR-122 targets PKM2 in the colon cancer cells, and forced expression of miR-122 re-sensitizes 5-fluorouracil (5-FU)-resistant cells to 5-FU by inhibiting PKM2 [ 43 ]. Silencing PKM2 and kidney-type glutaminase expression significantly reverses the resistance of colorectal cancer cells to oxaliplatin [ 46 ]. Inhibition of PKM2 in esophageal squamous cell carcinoma cells significantly decreases cisplatin resistance and increases apoptosis by inactivating the pentose phosphate pathway [ 47 ].…”