Wee1 inhibition can suppress tumor proliferation and sensitize p53 mutant colonic cancer cells to the anticancer effect of irinotecan

Abstract

Wee1 is an oncogenic nuclear kinase, which can regulate the cell cycle as a crucial G2M checkpoint. Overexpression of Wee1 can be observed in various cancer types, which may lead to a poor prognosis, but the potential therapeutic value of Wee1 in colorectal cancer has not been fully studied. In the present study, the role of Wee1 in colonic cancer was investigated. Wee1 inhibition by small interfering RNA was demonstrated to significantly restrain cancer cell proliferation and sensitize the p53 mutant colonic cancer cell lines HT29 and SW480 to the effect of treatment with ionizing radiation. The anticancer effect of the Wee1 inhibitor MK1775 was investigated in these two colonic cancer cell lines. MK1775 was demonstrated to induce significant DNA damage, suppress cell viability and induce apoptosis. In addition, MK1775 sensitized HT29 and SW480 cells to the effect of irinotecan. Annexin V/propidium iodide staining demonstrated that combination therapy can induce increased apoptosis compared with MK1775 or irinotecan monotherapy. The results of western blot analysis also indicated increased expression of the DNA damage marker histone H2AX, and apoptosis‑associated protein cleaved caspase 3, in HT29 and SW480 cells. In conclusion, the present study indicated that Wee1 may be a valuable target for treatment of p53 mutant colonic cancer.

Mutant p53 in Cancer Progression and Targeted Therapies

“…MK-1775 significantly elevated the efficacy of cisplatin, vorinostat (HADC inhibitor), or alisertib (aurora kinase A inhibitor) in HNSCC cells expressing high-risk mutp53 both in vitro and in vivo , while tumor cells bearing wildtype p53 displayed minimal response to MK-1775 ( 114 – 117 ). Consistently, MK-1775 was also reported to sensitize p53 mutant colon cancer cells to the DNA damage associated drug irinotecan ( 118 ). Currently, a randomized phase II study evaluating MK-1775 in combination with paclitaxel and carboplatin in adult patients with platinum sensitive p53 mutant ovarian cancer is ongoing (NCT01357161).…”

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

“…Regarding the mechanism of action, adavosertib induces S and/or G2/M cell cycle checkpoints override, depending on cancer types, when used in monotherapy. Cell cycle perturbation is associated with a progressive accumulation of DNA damages and by the induction of apoptosis [ 35 , 99 , 119 – 122 ]. This last event is cell cycle phase-dependent and can occur (i) as a consequence of S phase checkpoint override, when cancer cells start DNA replication even in the presence of DNA damages (replicative catastrophe); (ii) following G2/M phase checkpoint override, that results in forced entry into mitosis, even in the presence of DNA damages (mitotic catastrophe).…”

Long noncoding RNA LINC01410 promotes the tumorigenesis of neuroblastoma cells by sponging microRNA‐506‐3p and modulating WEE1

“…Mounting data proved that miRNAs involves in cancers through mediating expression of oncogenes or tumor suppressors 42,43 . WEE1 is increased in different malignancies, and WEE1 knockdown exerts antitumor effects in numerous tumors 44,45 . Garimella et al have proved that WEE1 knockdown decreases the cell viability and promotes the cell cycle arrest in breast cancer 46 .…”