TCF7 transcriptional activation of MACC1 regulates aerobic glycolysis and promotes oxaliplatin resistance in rectal cancer

Abstract

Background and purpose: Rectal cancer occurs on the inner wall of the rectum, and metastasis-associated in colon cancer 1 (MACC1) can promote drug resistance in colon cancer cells. This study aimed to investigate the effect of MACC1 on oxaliplatin resistance in rectal cancer and its mechanism. Methods: Biosignal analysis of MACC1 and TCF7 expressions in rectal cancer tissues and signaling pathways enriched for MACC1 were carried out. The expressions of MACC1 and TCF7 in rectal cancer cells and rectal cancer oxaliplatin-resistant cells were detected by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR), cell viability was detected by cell counting kit-8 (CCK-8), and cell proliferation was detected by cell colony formation assay. ECAR values, lactate production and glucose consumption were detected by Seahorse Biosciences XF96. Western blot was used to detect the expressions of glycolysis-related proteins. Dual luciferase reporter gene and ChIP were used to validate the regulatory relationship between MACC1 and TCF7. Normality test and homogeneity of variance analysis was performed on the data of each group by GraphPad Prism 8.0. If it conformed to normal distribution, one-way ANOVA or t-test would be used for inter group comparison, otherwise the comparison between groups would be conducted using Wilcoxon rank sum test. Using a two-sided test, P<0.05 was considered statistically significant. Results: MACC1 and TCF7 expressions were upregulated in rectal cancer, and knockdown of MACC1 significantly inhibited the viability of rectal cancer drug-resistant cells and the IC50 values of different concentrations of oxaliplatin treatments, as well as reduced the proliferation ability of rectal cancer oxaliplatin-resistant cells. Overexpression of MACC1 was able to promote the proliferation and glycolytic capacity of rectal cancer cells. Further studies revealed that the transcription factor TCF7 existed in the upper reaches of MACC1. Besides, this study analyzed the data from Cancer Genome Atlas Program (TCGA), and the result showed that knockdown of TCF7 was able to attenuate the promotional effect of overexpression of MACC1 on the glycolytic capacity and oxaliplatin resistance of rectal cancer cells. Conclusion: This study demonstrated that the TCF7/MACC1 axis could promote aerobic glycolysis and thus oxaliplatin resistance in rectal cancer cells. The findings suggest that targeting the TCF7/MACC1 axis or inhibiting the aerobic glycolysis pathway may be a novel therapeutic approach to inhibit oxaliplatin resistance in rectal cancer.

Keywords

• |macc1|tcf7|glycolysis|rectal cancer|oxaliplatin resistance