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.
Highlights
Colorectal cancer (CRC) ranks as the third most common cancer around the world
This study aimed to explore the possible association of oxaliplatinresistance with aerobic glycolysis/glutaminolysis indexed by pyruvate kinase M2 type (PKM2)/GLS1 expression
Protein expression quantified by Western blot (WB) technique further confirmed the differentiated expression of GLS1 and PKM2 in colorectal cancer (CRC) cell lines (Figure 1B)
Summary
Colorectal cancer (CRC) ranks as the third most common cancer around the world. Globally, over 1 million people are newly diagnosed to develop CRC per annum [1]. Zhou et al reported that intracellular ATP concentration was a critical determinant of chemoresistance of oxaliplatin in colon cancer cells [10]. Chemotherapy sensitivity of drug-resistant cells www.impactjournals.com/oncotarget could be elevated after consuming ATP. Chemotherapy resistance of drug-sensitive cells might be augmented after supplying exogenetic ATP [10]. There are two major sources of ATP in tumor cells: aerobic glycolysis and glutamine metabolism [11]. Fu et al found that downregulating GLS1 could re-sensitize the Taxol-resistant breast cancer cells to Taxol [17]. Guo et al observed that inhibiting GLS1 could dramatically sensitize the PP242induced cell death in ovarian cancer, and substantially reduce the phosphorylated STAT3 expression [18]
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