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

Yin,Yuping; Shen,Qian; Tao,Ruikang; Chang,Weilong; Li,Ruidong; Xie,Gengchen; Liu,Weizhen; Zhang,Peng; Tao,Kaixiong

doi:10.3892/mmr.2017.8230

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

Authors:
- Yuping Yin
- Qian Shen
- Ruikang Tao
- Weilong Chang
- Ruidong Li
- Gengchen Xie
- Weizhen Liu
- Peng Zhang
- Kaixiong Tao
View Affiliations

Affiliations: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou, Zhengzhou, Henan 450000, P.R. China
Published online on: December 8, 2017 https://doi.org/10.3892/mmr.2017.8230
Pages: 3344-3349

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R and Jemal A: Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 66:271–289. 2016. View Article : Google Scholar : PubMed/NCBI
2	Zhou Y, Abel GA, Hamilton W, Pritchard-Jones K, Gross CP, Walter FM, Renzi C, Johnson S, McPhail S, Elliss-Brookes L and Lyratzopoulos G: Diagnosis of cancer as an emergency: A critical review of current evidence. Nat Rev Clin Oncol. 14:45–56. 2017. View Article : Google Scholar : PubMed/NCBI
3	Kolligs FT: Diagnostics and epidemiology of colorectal cancer. Visc Med. 32:158–164. 2016. View Article : Google Scholar : PubMed/NCBI
4	Moriarity A, O'Sullivan J, Kennedy J, Mehigan B and McCormick P: Current targeted therapies in the treatment of advanced colorectal cancer: A review. Ther Adv Med Oncol. 8:276–293. 2016. View Article : Google Scholar : PubMed/NCBI
5	Kastan MB and Bartek J: Cell-cycle checkpoints and cancer. Nature. 432:316–323. 2004. View Article : Google Scholar : PubMed/NCBI
6	Santo L, Siu KT and Raje N: Targeting cyclin-dependent kinases and cell cycle progression in human cancers. Semin Oncol. 42:788–800. 2015. View Article : Google Scholar : PubMed/NCBI
7	Benada J and Macurek L: Targeting the checkpoint to kill cancer cells. Biomolecules. 5:1912–1937. 2015. View Article : Google Scholar : PubMed/NCBI
8	Russell P and Nurse P: Negative regulation of mitosis by Wee1+, a gene encoding a protein kinase homolog. Cell. 49:559–567. 1987. View Article : Google Scholar : PubMed/NCBI
9	Gould KL and Nurse P: Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature. 342:39–45. 1989. View Article : Google Scholar : PubMed/NCBI
10	Leary A, Auguste A and Mesnage S: DNA damage response as a therapeutic target in gynecological cancers. Curr Opin Oncol. 28:404–411. 2016. View Article : Google Scholar : PubMed/NCBI
11	Magnussen GI, Holm R, Emilsen E, Rosnes AK, Slipicevic A and Flørenes VA: High expression of Wee1 is associated with poor disease-free survival in malignant melanoma: Potential for targeted therapy. PLoS One. 7:e382542012. View Article : Google Scholar : PubMed/NCBI
12	Yoshida T, Tanaka S, Mogi A, Shitara Y and Kuwano H: The clinical significance of Cyclin B1 and Wee1 expression in non-small-cell lung cancer. Ann Oncol. 15:252–256. 2004. View Article : Google Scholar : PubMed/NCBI
13	Kim HY, Cho Y, Kang H, Yim YS, Kim SJ, Song J and Chun KH: Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer. Oncotarget. 7:49902–49916. 2016. View Article : Google Scholar : PubMed/NCBI
14	Hirai H, Iwasawa Y, Okada M, Arai T, Nishibata T, Kobayashi M, Kimura T, Kaneko N, Ohtani J, Yamanaka K, et al: Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 8:2992–3000. 2009. View Article : Google Scholar : PubMed/NCBI
15	Osman AA, Monroe MM, Ortega Alves MV, Patel AA, Katsonis P, Fitzgerald AL, Neskey DM, Frederick MJ, Woo SH, Caulin C, et al: Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence. Mol Cancer Ther. 14:608–619. 2015. View Article : Google Scholar : PubMed/NCBI
16	Egeland EV, Flatmark K, Nesland JM, Flørenes VA, Mælandsmo GM and Boye K: Expression and clinical significance of Wee1 in colorectal cancer. Tumour Biol. 37:12133–12140. 2016. View Article : Google Scholar : PubMed/NCBI
17	Hirai H, Arai T, Okada M, Nishibata T, Kobayashi M, Sakai N, Imagaki K, Ohtani J, Sakai T, Yoshizumi T, et al: MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther. 9:514–522. 2010. View Article : Google Scholar : PubMed/NCBI
18	Cuneo KC, Morgan MA, Davis MA, Parcels LA, Parcels J, Karnak D, Ryan C, Liu N, Maybaum J and Lawrence TS: Wee1 kinase inhibitor AZD1775 radiosensitizes hepatocellular carcinoma regardless of TP53 mutational status through induction of replication stress. Int J Radiat Oncol Biol Phys. 95:782–790. 2016. View Article : Google Scholar : PubMed/NCBI
19	Leijen S, van Geel RM, Sonke GS, de Jong D, Rosenberg EH, Marchetti S, Pluim D, van Werkhoven E, Rose S, Lee MA, et al: Phase II study of WEE1 inhibitor AZD1775 plus carboplatin in patients with TP-53 mutated ovarian cancer refractory or resistant to first-line therapy with 3 months. J Clin Oncol. 34:4354–4361. 2016. View Article : Google Scholar : PubMed/NCBI
20	Wulaningsih W, Wardhana A, Watkins J, Yoshuantari N, Repana D and Van Hemelrijck M: Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression-free survival in patients with advanced and/or metastatic colorectal cancer. Cochrane Database Syst Rev. 2:CD0085932016.PubMed/NCBI
21	Beetham KL and Tolmach LJ: The action of caffeine on X-irradiated hela cells. V. Identity of the sector of cells that expresses potentially lethal damage in G1 and G2. Radiat Res. 91:199–211. 1982. View Article : Google Scholar : PubMed/NCBI
22	Dixon H and Norbury CJ: Therapeutic exploitation of checkpoint defects in cancer cells lacking p53 function. Cell Cycle. 1:362–368. 2002. View Article : Google Scholar : PubMed/NCBI
23	Van Linden AA, Baturin D, Ford JB, Fosmire SP, Gardner L, Korch C, Reigan P and Porter CC: Inhibition of wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol Cancer Ther. 12:2675–2684. 2013. View Article : Google Scholar : PubMed/NCBI
24	Guertin AD, Li J, Liu Y, Hurd MS, Schuller AG, Long B, Hirsch HA, Feldman I, Benita Y, Toniatti C, et al: Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy. Mol Cancer Ther. 12:1442–1452. 2013. View Article : Google Scholar : PubMed/NCBI
25	Kreahling JM, Gemmer JY, Reed D, Letson D, Bui M and Altiok S: MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Mol Cancer Ther. 11:174–182. 2012. View Article : Google Scholar : PubMed/NCBI
26	Fischer von Weikersthal L, Schalhorn A, Stauch M, Quietzsch D, Maubach PA, Lambertz H, Oruzio D, Schlag R, Weigang-Köhler K, Vehling-Kaiser U, et al: Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer. 47:206–214. 2011. View Article : Google Scholar : PubMed/NCBI
27	Sun M, Zhang Q, Yang X, Qian SY and Guo B: Vitamin D enhances the efficacy of irinotecan through miR-627-mediated inhibition of intratumoral drug metabolism. Mol Cancer Ther. 15:2086–2095. 2016. View Article : Google Scholar : PubMed/NCBI
28	Quackenbush KS, Bagby S, Tai WM, Messersmith WA, Schreiber A, Greene J, Kim J, Wang G, Purkey A, Pitts TM, et al: The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance. Oncotarget. 7:28273–28285. 2016. View Article : Google Scholar : PubMed/NCBI