Abstract
Chemoresistance is one of the major problems of colon cancer treatment. In tumors, glycolytic metabolism has been identified to promote cell proliferation and chemoresistance. However, the molecular mechanisms underlying glycolytic metabolism and chemoresistance in colon cancer remains enigmatic. Hence, this research was designed to explore the mechanism underlying the OLR1/c-MYC/SULT2B1 axis in the regulation of glycolytic metabolism, to affect colon cancer cell proliferation and chemoresistance. Colon cancer tissues and LoVo cells were attained, where OLR1, c-MYC, and SULT2B1 expression was detected by immunohistochemistry, RT-qPCR, and western blot analysis. Next, ectopic expression and knockdown assays were implemented in LoVo cells. Cell proliferation was detected by MTS assay and clone formation. Extracellular acidification, glucose uptake, lactate production, ATP/ADP ratio, and GLUT1 and LDHA expression were measured to evaluate glycolytic metabolism. Then, the transfected cells were treated with chemotherapeutic agents to assess drug resistance by MTS experiments and P-gp and SMAD4 expression by RT-qPCR. A nude mouse model of colon cancer transplantation was constructed for in vivo verification. The levels of OLR1, c-MYC, and SULT2B1 were upregulated in colon cancer tissues and cells. Mechanistically, OLR1 increased c-MYC expression to upregulate SULT2B1 in colon cancer cells. Moreover, knockdown of OLR1, c-MYC, or SULT2B1 weakened glycolytic metabolism, proliferation, and chemoresistance of colon cancer cells. In vivo experiments authenticated that OLR1 knockdown repressed the tumorigenesis and chemoresistance in nude mice by downregulating c-MYC and SULT2B1. Conclusively, knockdown of OLR1 might diminish SULT2B1 expression by downregulating c-MYC, thereby restraining glycolytic metabolism to inhibit colon cancer cell proliferation and chemoresistance.
Highlights
Colon cancer initiates with an extensive block of cell replication with replication foci shifting towards the upper parts of crypts [1]
OLR1 is negatively correlated with the survival of patients with colon cancer In order to find the targets for the treatment and diagnosis of colon cancer, 1130, 178, and 992 upregulated genes in colon cancer were found by differential analysis of expression datasets GSE10950, GSE41328, and GSE75970, respectively, which obtained 45 genes from their intersection (Fig. 1A)
The results suggested that OLR1 might be involved in the occurrence and development of colon cancer
Summary
Colon cancer initiates with an extensive block of cell replication with replication foci shifting towards the upper parts of crypts [1]. Colon cancer is clarified into three discernible stages: initiation, promotion, and progression, where the normal colonic epithelium pathologically transforms into hyperproliferative epitheliums, into adenomas and carcinoma in situ, and into invasive and metastatic cancer [2]. It is well-known that the risk factor for colon cancer includes red meat intake, dietary factors, age, ethnicity, sex, history of colon cancer, enhanced body mass index (BMI), low vegetable and fruit consumption, genetic makeup, low physical activity, and long-term cigarette smoking (30–40 years) [3]. Resistance to chemotherapeutic agents is one of the principal obstacles related to colon cancer treatment, which engenders the need to develop novel therapies’ targets [6]
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