title: T-oligo as an anticancer agent in colorectal cancer.
abstract: In the United States, there will be an estimated 96,830 new cases of colorectal cancer (CRC) and 50,310 deaths in 2014. CRC is often detected at late stages of the disease, at which point there is no effective chemotherapy. Thus, there is an urgent need for effective novel therapies that have minimal effects on normal cells. T-oligo, an oligonucleotide homologous to the 3'-telomere overhang, induces potent DNA damage responses in multiple malignant cell types, however, its efficacy in CRC has not been studied. This is the first investigation demonstrating T-oligo-induced anticancer effects in two CRC cell lines, HT-29 and LoVo, which are highly resistant to conventional chemotherapies. In this investigation, we show that T-oligo may mediate its DNA damage responses through the p53/p73 pathway, thereby inhibiting cellular proliferation and inducing apoptosis or senescence. Additionally, upregulation of downstream DNA damage response proteins, including E2F1, p53 or p73, was observed. In LoVo cells, T-oligo induced senescence, decreased clonogenicity, and increased expression of senescence associated proteins p21, p27, and p53. In addition, downregulation of POT1 and TRF2, two components of the shelterin protein complex which protects telomeric ends, was observed. Moreover, we studied the antiproliferative effects of T-oligo in combination with an EGFR tyrosine kinase inhibitor, Gefitinib, which resulted in an additive inhibitory effect on cellular proliferation. Collectively, these data provide evidence that T-oligo alone, or in combination with other molecularly targeted therapies, has potential as an anti-cancer agent in CRC.
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Illinois, United States.
authors.forename: Luke
authors.initials: L
authors.lastname: Wojdyla
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Illinois, United States.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Stone
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Sethakorn
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Illinois, United States.
authors.forename: Srijayaprakash B
authors.initials: SB
authors.lastname: Uppada
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Illinois, United States.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Devito
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Illinois, United States.
authors.forename: Neelu
authors.initials: N
authors.lastname: Puri
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D019073:HT29 Cells; D006801:Humans; D009841:Oligonucleotides / Q000627:therapeutic use*; D059505:Telomere Homeostasis / Q000187:drug effects* / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009841:Oligonucleotides; D034501:Telomere-Binding Proteins
keywords: DNA damage responses; Differentiation; EGFR; T-oligo; Telomere; Therapeutic