Significance of Notch and Wnt signaling for chemoresistance of colorectal cancer cells HCT116

Abstract

5-fluorouracil (5-FU) and oxaliplatin (OxaPt) are the main chemotherapeutics for colorectal cancer (CRC). Chemotherapy response rates for advanced CRC remain low, primarily due to intrinsic or acquired chemoresistance. The importance of Notch and Wnt signaling for carcinogenesis of CRC as well as crosstalk of Notch and Wnt signaling with many oncogenic signaling pathways suggest that Notch and Wnt pathways could be responsible for chemoresistance. In this study, we compared changes in Notch and Wnt signaling after 5-FU and OxaPt treatment in CRC cells HCT116 and its chemoresistant sublines HCT116/FU and HCT116/OXA. The levels of Notch1 receptor intracellular domain NICD1 and non-phosphorylated β-catenin, the reporters of Notch and Wnt signaling, were upregulated in untreated chemoresistant HCT116/FU and HCT116/OXA cells. Our data suggest that Notch inhibitor RO4929097 (RO) and Wnt inhibitor XAV939 (XAV) enhance the survival potential of OxaPt-treated cells. The protein level of Notch target gene HES1 was significantly upregulated in chemoresistant HCT116/FU and HCT116/OXA cells, compared to HCT116. HES1 silencing increased viability of HCT116 and its chemoresistant sublines after 5-FU or OxaPt treatment. The results of HES1 downregulation coincide with RO and XAV effects on cell viability of OxaPt-treated cells.

Annexin A3 depletion overcomes resistance to oxaliplatin in colorectal cancer via the MAPK signaling pathway

“…Oxaliplatin (Ox) is a standard drug for palliative chemotherapy of metastatic colon cancer and late‐stage CRC . Despite intrinsic and acquired chemoresistance, chemotherapy response rates remains low . Therefore, identifying novel predictive biomarkers may help identify clinically beneficial adjuvant chemotherapy for CRC.…”

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

“…Regarding cisplatin chemoresistance, high expression of UCA1 in resistant cells significantly increases cell viability during cisplatin treatment. Moreover, overexpression positively regulates expression of Wnt6, subsequently activating Wnt signaling [21], which was previously connected with chemoresistance in cancer [87]. In addition to cisplatin, UCA1 was also studied in relation to gemcitabine resistance, where functioning via the UCA1/CREB/miR-196a-5p axis is proposed [20].…”

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

“…As discussed previously, Notch signalling is critically involved in CSC renewal and differentiation ( Section 4.8 ), making Notch inhibitors an attractive combination treatment strategy with standard cytotoxic therapy. Chemotherapy induces Notch activation and inhibition of Notch sensitises cancer cells to chemotherapy in multiple studies across different cancer types including T-ALL [ 265 ], breast cancer [ 266 ] ovarian cancer [ 259 ], glioma [ 267 ], hepatocellular carcinoma [ 268 ], prostate cancer [ 269 , 270 , 271 ], colorectal cancer [ 272 , 273 ], lung cancer [ 151 , 274 , 275 ] and osteosarcoma [ 276 ]. Similar results have also indicated the role of aberrant Notch signalling in radiation therapy resistance [ 249 , 267 , 277 ].…”