Novel combination treatment for colorectal cancer using Nek2 siRNA and cisplatin

Abstract

Nek2 (NIMA-related kinase 2) is involved in cell division and mitotic regulation by centrosome splitting. We previously reported that Nek2 depletion causes growth suppression and cell death in cholangiocarcinoma and breast cancer cells. In this report, we examine the effect of a combination treatment using Nek2 siRNA with the cytotoxic chemotherapeutic agent cisplatin (CDDP) on colorectal cancer. Nek2 was overexpressed in all colorectal cancer cell lines examined (HCT-15, DLD-1, Colo205, and Colo320). Nek2 short-interfering RNA (siRNA) resulted in the inhibition of cell proliferation and the induction of apoptosis in vitro. Nek2 siRNA suppressed tumor growth compared to control siRNA in a xenograft mouse model. To investigate the potential utility of Nek2 siRNA for clinical cancer therapy, we examine the effect of a combination treatment using Nek2 siRNA with CDDP on colorectal cancer. The combined administration of both Nek2 siRNA and CDDP inhibited cell proliferation and induced apoptotic cell death in vitro. Furthermore, the combined administration of both Nek2 siRNA and CDDP suppressed tumor growth compared to either the single administration of Nek2 siRNA or the combined administration of control siRNA and CDDP. Our results suggest that combination treatment using Nek2 siRNA and chemotherapeutic agents may be an effective therapeutic option for colorectal cancer.

High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase

“…Several kinases that had been previously shown to regulate telomerase were also among the hits, confirming the specificity of the functional read-out of the HTS (6)(7)(8). Moreover several of the identified kinases have been found overexpressed in different human cancers and are now being exploited as potential targets for cancer therapeutics (20)(21)(22)(25)(26)(27)(28)(29). Subsequent validation experiments showed that modulation of some of these proteins resulted in perturbation of telomerase function and elicited phenotypic changes characteristic of telomere dysfunctions, suggesting that the proteins identified in our screen are likely true modifiers of telomerase.…”

“…There is now substantial evidence that NEK2, NEK6, NEK7, and NEK9 regulate mitotic progression and mitotic spindle organization (24). Furthermore, high expression levels of NEK kinases have also been found in human cancers, such as breast and bladder cancers (25,26) and NEK kinases are now being pursued as potential therapeutic targets (27,28). Members of the MAPK superfamily were also selected given their diverse functions in a wide variety of biological processes (9,29).…”

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

“…Several data sets have also indicated that NEK2 is up-regulated in breast tumors expressing mutant p53 compared with WT. This is of particular importance because NEK2-based anticancer therapies are under preclinical development (42,43). If NEK2 protein is similarly up-regulated in mutant p53-expressing tumors, then these patients may achieve better benefits from NEK2-based therapies.…”

Upregulation of NEK2 is associated with drug resistance in ovarian cancer

“…Likewise, the relationship between NEK2 and drug resistance is unclear, with only several studies indicating its drug resistance-related functions. The combined use of both NEK2 siRNA and cisplatin inhibited cell proliferation and induced apoptotic cell death in vitro, suggesting that NEK2 may be associated with drug resistance in colorectal cancer (38). Similarly, the combination of NEK2 siRNA with paclitaxel and doxorubicin was found to improve the sensitivity of breast cancer cells during chemotherapy treatment (20).…”