Abstract
Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor (EGFR) oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog (KRAS) mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, KRAS is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of KRAS/MMP7/CD44 oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in KRAS and CD44 were associated with some of the top tumorigenic oncogene’s overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the KRAS/MMP7/CD44 oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of KRAS/MMP7/CD44 in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.
Highlights
Colorectal cancer (CRC) remains a common cause of cancer-related fatalities globally [1], despite currently available advanced treatment options, including surgical resection, radiotherapy, chemotherapy, and targeted therapies [2]
We determined the potential roles of the KRAS/MMP7/cluster of differentiation 44 (CD44) oncogenes as factors that influence high diagnostic efficacy in CRC patients; we explored a receiver operating characteristic (ROC) analysis based on the TCGA database, on patients’ responses to chemotherapy treatment based on RECIST criteria, and results showed that patients with increased levels of these genes responded poorly to treatment (Figure 3)
The dose depended on treatment of sulfasalazine suppressed the expression of KRAS/MMP7/CD44 in DLD-1 and HCT116 cell lines
Summary
Colorectal cancer (CRC) remains a common cause of cancer-related fatalities globally [1], despite currently available advanced treatment options, including surgical resection, radiotherapy, chemotherapy, and targeted therapies [2]. CRC is often diagnosed in an advanced stage, with approximately 25% of patients displaying distant metastasis; this presents a challenge to clinicians [3–5]. Patients who undergo surgery and still exhibit an unresectable metastatic tumor are further treated with chemotherapy and targeted therapy [6]; these therapeutics only offer limited enhancement of overall survival for patients [7]. The molecular mechanisms of CRC are unclear, as the disease is heterogeneous. This poses a challenge in terms of patients’ responses to treatments [8]; there is an urgent need for novel therapeutic interventions aimed at combating metastatic (m)CRC [9]. 5% of mCRC patients reach the 5-year survival mark [10]
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