The role and mechanism of WEE1 on the cisplatin resistance reversal of the HepG2/DDP human hepatic cancer cell line

Abstract

Abstract. Drug resistance to cisplatin with continuous drug treatment is one of the most common causes of chemotherapy failure in hepatic carcinoma. Accumulating evidence suggests that WEE1 G2 checkpoint kinase (WEE1) is involved in cisplatin resistance, which has been demonstrated to correlate with cancer initiation and progression. However, the role and molecular mechanism of WEE1 in the drug resistance of hepatic cancer remains unclear. In the present study, using the WEE-knockdown hepatic cancer cell line HepG2/DDP, the role of WEE1 and its molecular mechanism were investigated. It was demonstrated that silencing WEE1 expression resulted in an increased cisplatin sensitivity of HepG2/DDP, in addition to an increased rate of apoptosis and intracellular concentration of rhodamine 123. The expression levels of P-gp, MDR1, MRP1, LRP, BCL-2, survivin and GST in WEE1-silenced HepG2/DDP cells were significantly reduced, and phosphorylation levels of MEK and ERK were significantly downregulated. The results demonstrated that WEE1 negatively regulated the multidrug resistance potential of human hepatic cancer cells by modulating the expression of relevant drug resistance genes and the activity of the MEK/ERK pathway. Therefore, WEE1 may be a monitoring bio-marker for drug resistance, and a therapeutic target in hepatic cancer.

Silencing GOLPH3 gene expression reverses resistance to cisplatin in HT29 colon cancer cells via multiple signaling pathways

“…Liu et al (26) found that high-mobility group box 1 protein (a regulator of autophagy) was released in colorectal cancer cell lines following chemotherapy with oxaliplatin and decreased the sensitivity of colorectal cancer cells to oxaliplatin by activating the MEK/ERK pathway. Zhao et al (27) confirmed that silencing WEE1 expression reversed multidrug resistance and increased the sensitivity of HepG2/DDP cells to cisplatin. The underlying mechanism was associated with inhibition of the MAPK/ERK signaling pathway and the downregulated expression of genes that are associated with multidrug resistance.…”

HJURP Promotes Malignant Progression and Mediates Sensitivity to Cisplatin and WEE1-inhibitor in Serous Ovarian Cancer

“…We have testified that HJURP could modulate MYC/WEE1 axis and MYC was an upstream transcription factor of WEE1. Considering that WEE1 inhibitor could synergize with many DNA damage agents including cisplatin [31][32][33][34][35], we would like to explore whether MYC/WEE1 axis was the intermediate process of chemoresistance induced by HJURP. As shown in Supplementary Figures S5A, B, clonogenic formation number increased in HJURP overexpression group compared with control at 2μg/ml concentration of cisplatin in SKOV3.…”

“…The synergistic lethality phenomenon indicated WEE1 could be a novel therapeutic target in combinatory strategies containing DNA-damaging agents. Various studies indicated that WEE1 could modulate cisplatin sensitivity by multiple mechanisms and targeting WEE1 was promising for overcoming cisplatin resistance [33][34][35]. Besides, WEE1 could also inactivate CDK2 during S phase, performing maintenance of replication forks and controlling genomic stability [36][37][38].…”