Suppression of STN1 enhances the cytotoxicity of chemotherapeutic agents in cancer cells by elevating DNA damage

Zhou,Qing; Chai,Weihang

doi:10.3892/ol.2016.4676

Suppression of STN1 enhances the cytotoxicity of chemotherapeutic agents in cancer cells by elevating DNA damage

Authors:
- Qing Zhou
- Weihang Chai
View Affiliations

Affiliations: Department of Biomedical Sciences, Elson S. Floyd College of Medical Sciences, Washington State University, Spokane, WA 99210, USA
Published online on: June 2, 2016 https://doi.org/10.3892/ol.2016.4676
Pages: 800-808
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

DNA damage-inducing agents are among the most effective treatment regimens in clinical chemotherapy. However, drug resistance and severe side effects caused by these agents greatly limit their efficacy. Sensitizing malignant cells to chemotherapeutic agents has long been a goal of chemotherapy. In the present study, suppression of STN1, a gene important for safeguarding genome stability, potentiated the anticancer effect of chemotherapeutic agents in tumor cells. Using multiple cancer cells from a variety of origins, it was observed that downregulation of STN1 resulted in a significant decrease in the half maximal inhibitory concentration values of several conventional anticancer agents. When cells are treated with anticancer agents, STN1 suppression leads to a decline in colony formation and diminished anchorage-independent growth. Furthermore, it was additionally observed that STN1 knockdown augmented the levels of DNA damage caused by damage‑inducing agents. The present study concluded that suppression of STN1 enhances the cytotoxicity of damage‑inducing chemotherapeutic agents by increasing DNA damage in cancer cells.

View Figures

View References

1	Cheung-Ong K, Giaever G and Nislow C: DNA-damaging agents in cancer chemotherapy: Serendipity and chemical biology. Chem Biol. 20:648–659. 2013. View Article : Google Scholar : PubMed/NCBI
2	Lord CJ and Ashworth A: The DNA damage response and cancer therapy. Nature. 481:287–294. 2012. View Article : Google Scholar : PubMed/NCBI
3	Bouwman P and Jonkers J: The effects of deregulated DNA damage signaling on cancer chemotherapy response and resistance. Nat Rev Cancer. 12:587–598. 2012. View Article : Google Scholar : PubMed/NCBI
4	Luo Y and Leverson JD: New opportunities in chemosensitization and radiosensitization: Modulating the DNA-damage response. Expert Rev Anticancer Ther. 5:333–342. 2005. View Article : Google Scholar : PubMed/NCBI
5	Holohan C, Van Schaeybroeck S, Longley DB and Johnston PG: Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 13:714–727. 2013. View Article : Google Scholar : PubMed/NCBI
6	Coley HM: Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat Rev. 34:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
7	Zhou BB and Bartek J: Targeting the checkpoint kinases: Chemosensitization versus chemoprotection. Nat Rev Cancer. 4:216–225. 2004. View Article : Google Scholar : PubMed/NCBI
8	Gu P, Min JN, Wang Y, Huang C, Peng T, Chai W and Chang S: CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. EMBO J. 31:2309–2321. 2012. View Article : Google Scholar : PubMed/NCBI
9	Huang C, Dai X and Chai W: Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in. Cell Res. 22:1681–1695. 2012. View Article : Google Scholar : PubMed/NCBI
10	Stewart JA, Wang F, Chaiken MF, Kasbek C, Chastain PD II, Wright WE and Price CM: Human CST promotes telomere duplex replication and general replication restart after fork stalling. EMBO J. 31:3537–3549. 2012. View Article : Google Scholar : PubMed/NCBI
11	Casteel DE, Zhuang S, Zeng Y, Perrino FW, Boss GR, Goulian M and Pilz RB: A DNA polymerase-{alpha}{middle dot}primase cofactor with homology to replication protein A-32 regulates DNA replication in mammalian cells. J Biol Chem. 284:5807–5818. 2009. View Article : Google Scholar : PubMed/NCBI
12	Wan M, Qin J, Songyang Z and Liu D: OB-fold containing protein 1 (OBFC1), a human homolog of yeast Stn1, associates with TPP1 and is implicated in telomere length regulation. J Biol Chem. 284:26725–26731. 2009. View Article : Google Scholar : PubMed/NCBI
13	Chen LY, Majerská J and Lingner J: Molecular basis of telomere syndrome caused by CTC1 mutations. Genes Dev. 27:2099–2108. 2013. View Article : Google Scholar : PubMed/NCBI
14	Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, Urquhart JE, Daly SB, Dickerson JE, O'Sullivan J, et al: Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet. 44:338–342. 2012. View Article : Google Scholar : PubMed/NCBI
15	Chen LY, Redon S and Lingner J: The human CST complex is a terminator of telomerase activity. Nature. 488:540–544. 2012. View Article : Google Scholar : PubMed/NCBI
16	Wang F, Stewart JA, Kasbek C, Zhao Y, Wright WE and Price CM: Human CST has independent functions during telomere duplex replication and C-strand fill-in. Cell Rep. 2:1096–1103. 2012. View Article : Google Scholar : PubMed/NCBI
17	Wu P, Takai H and de Lange T: Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell. 150:39–52. 2012. View Article : Google Scholar : PubMed/NCBI
18	Shay JW and Wright WE: Telomerase therapeutics for cancer: Challenges and new directions. Nat Rev Drug Discov. 5:577–584. 2006. View Article : Google Scholar : PubMed/NCBI
19	De Cian A, Lacroix L, Douarre C, Temime-Smaali N, Trentesaux C, Riou JF and Mergny JL: Targeting telomeres and telomerase. Biochimie. 90:131–155. 2008. View Article : Google Scholar : PubMed/NCBI
20	Mondello C and Scovassi IA: Telomeres, telomerase, and apoptosis. Biochem Cell Biol. 82:498–507. 2004. View Article : Google Scholar : PubMed/NCBI
21	Chan SR and Blackburn EH: Telomeres and telomerase. Philos Trans R Soc Lond B Biol Sci. 359:109–121. 2004. View Article : Google Scholar : PubMed/NCBI
22	Liu Y, Bohr VA and Lansdorp P: Telomere, telomerase and aging. Mech Ageing Dev. 129:1–2. 2008. View Article : Google Scholar : PubMed/NCBI
23	Chen M and McLeskey SW: Telomere-based cancer treatment: emerging targeted therapies. Clin J Oncol Nursing. 14:720–727. 2010. View Article : Google Scholar
24	Herbert BS, Gellert GC, Hochreiter A, Pongracz K, Wright WE, Zielinska D, Chin AC, Harley CB, Shay JW and Gryaznov SM: Lipid modification of GRN163, an N3′-P5′ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene. 24:5262–5268. 2005. View Article : Google Scholar : PubMed/NCBI
25	Dai X, Huang C, Bhusari A, Sampathi S, Schubert K and Chai W: Molecular steps of G-overhang generation at human telomeres and its function in chromosome end protection. EMBO J. 29:2788–2801. 2010. View Article : Google Scholar : PubMed/NCBI
26	Collins AR: The comet assay. Principles, applications, and limitations. Methods Mol Biol. 203:163–177. 2002.PubMed/NCBI
27	Gu P and Chang S: Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus. Aging Cell. 12:1100–1109. 2013. View Article : Google Scholar : PubMed/NCBI
28	Pizarro JG, Folch J, Junyent F, Verdaguer E, Auladell C, Beas-Zarate C, Pallàs M and Camins A: Antiapoptotic effects of roscovitine on camptothecin-induced DNA damage in neuroblastoma cells. Apoptosis. 16:536–550. 2011. View Article : Google Scholar : PubMed/NCBI
29	Berniak K, Rybak P, Bernas T, Zarębski M, Biela E, Zhao H, Darzynkiewicz Z and Dobrucki JW: Relationship between DNA damage response, initiated by camptothecin or oxidative stress, and DNA replication, analyzed by quantitative 3D image analysis. Cytometry A. 83:913–924. 2013.PubMed/NCBI
30	Nguyen TV, Chen JK and Murray V: Bleomycin DNA damage: Anomalous mobility of 3′-phosphoglycolate termini in an automated capillary DNA sequencer. J Chromatogr B Analyt Technol Biomed Life Sci. 913–914:113–122. 2013. View Article : Google Scholar
31	Patel JR, Dhorajiya BD, Dholakiya BZ, Badria FA and Ibrahim AS: In-vitro cytotoxicity, antioxidant, bleomycin-dependent DNA damage and immunomodulatory evaluation of 1-(4-acetylphenyl)-3-aryloxypyrrolidine-2, 5-dione based derivatives. Med Chem Res. 23:3907–3915. 2014. View Article : Google Scholar
32	Li X, Liu W, Wang H, Yang L, Li Y, Wen H, Ning H, Wang J, Zhang L, Li J and Fan D: Rap1 is indispensable for TRF2 function in etoposide-induced DNA damage response in gastric cancer cell line. Oncogenesis. 4:e1442015. View Article : Google Scholar : PubMed/NCBI
33	Griaud F, Williamson AJK, Taylor S, Potier DN, Spooncer E, Pierce A and Whetton AD: BCR/ABL modulates protein phosphorylation associated with the etoposide-induced DNA damage response. J Proteomics. 77:14–26. 2012. View Article : Google Scholar : PubMed/NCBI
34	Grand CL, Han H, Muñoz RM, Weitman S, Von Hoff DD, Hurley LH and Bearss DJ: The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo. Mol Cancer Ther. 1:565–573. 2002.PubMed/NCBI
35	Tarsounas M and Tijsterman M: Genomes and G-quadruplexes: For better or for worse. J Mol Biol. 425:4782–4789. 2013. View Article : Google Scholar : PubMed/NCBI
36	Bochman ML, Paeschke K and Zakian VA: DNA secondary structures: Stability and function of G-quadruplex structures. Nat Rev Genet. 13:770–780. 2012. View Article : Google Scholar : PubMed/NCBI
37	Borowicz S, Scoyk MV, Avasarala S, Rathinam Karuppusamy MK, Tauler J, Bikkavilli RK and Winn RA: The soft agar colony formation assay. J Vis Exp. 92:e519982014.PubMed/NCBI
38	Horibata S, Vo TV, Subramanian V, Thompson PR and Coonrod SA: Utilization of the soft agar colony formation assay to identify inhibitors of tumorigenicity in breast cancer cells. J Vis Exp. 99:e527272015.PubMed/NCBI
39	IARC/NCI/EPA Working Group: Cellular and molecular mechanisms of cell transformation and standardization of transformation assays of established cell lines for the prediction of carcinogenic chemicals: Overview and recommended protocols. Cancer Res. 45:2395–2399. 1985.
40	Kolber AR, Wong TK, Grant LD, DeWoskin RS and Hughes TJ: In Vitro Toxicity Testing of Environmental Agents. Current and Future Possibilities Part A: Survey of Test Systems. Plenum Press. (New York). 321–322. 1979.
41	Pullman B, Ts'O POP and Schneider EL: Interrelationship Among Aging, Cancer and Differentiation. The Jerusalem Symposia on Quantum Chemistry and Biochemistry. 18:D. Reidel Publishing Company. (Dordrecht, The Netherlands). 247–248. 1985.
42	Collins AR: The comet assay for DNA damage and repair: Principles, applications, and limitations. Mol Biotechnol. 26:249–261. 2004. View Article : Google Scholar : PubMed/NCBI
43	Hosoya N and Miyagawa K: Targeting DNA damage response in cancer therapy. Cancer Sci. 105:370–388. 2014. View Article : Google Scholar : PubMed/NCBI
44	Dickerson EB, Blackburn WH, Smith MH, Kapa LB, Lyon LA and McDonald JF: Chemosensitization of cancer cells by siRNA using targeted nanogel delivery. BMC Cancer. 10:102010. View Article : Google Scholar : PubMed/NCBI
45	Wang F, Stewart J and Price CM: Human CST abundance determines recovery from diverse forms of DNA damage and replication stress. Cell Cycle. 13:3488–3498. 2014. View Article : Google Scholar : PubMed/NCBI