Oligonucleotides and MicroRNAs Targeting Telomerase Subunits in Cancer Therapy

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2020 Aug 23

PMID 32825005

Citations 8

Authors

Adam Eckburg

Joshua Dein

Joseph Berei

Zachary Schrank

Neelu Puri

Affiliations

Soon will be listed here.

Abstract

Telomerase provides cancer cells with replicative immortality, and its overexpression serves as a near-universal marker of cancer. Anti-cancer therapeutics targeting telomerase have garnered interest as possible alternatives to chemotherapy and radiotherapy. Oligonucleotide-based therapies that inhibit telomerase through direct or indirect modulation of its subunits, human telomerase reverse transcriptase (hTERT) and human telomerase RNA gene (hTERC), are a unique and diverse subclass of telomerase inhibitors which hold clinical promise. MicroRNAs that play a role in the upregulation or downregulation of hTERT and respective progression or attenuation of cancer development have been effectively targeted to reduce telomerase activity in various cancer types. Tumor suppressor miRNAs, such as miRNA-512-5p, miRNA-138, and miRNA-128, and oncogenic miRNAs, such as miRNA-19b, miRNA-346, and miRNA-21, have displayed preclinical promise as potential hTERT-based therapeutic targets. Antisense oligonucleotides like GRN163L and T-oligos have also been shown to uniquely target the telomerase subunits and have become popular in the design of novel cancer therapies. Finally, studies suggest that G-quadruplex stabilizers, such as Telomestatin, preserve telomeric oligonucleotide architecture, thus inhibiting hTERC binding to the telomere. This review aims to provide an adept understanding of the conceptual foundation and current state of therapeutics utilizing oligonucleotides to target the telomerase subunits, including the advantages and drawbacks of each of these approaches.

Citing Articles

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Telomeres and telomerase in Sarcoma disease and therapy.

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Transitional Insight into the RNA-Based Oligonucleotides in Cancer Treatment.

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References

Li J, Lei H, Xu Y, Tao Z . miR-512-5p suppresses tumor growth by targeting hTERT in telomerase positive head and neck squamous cell carcinoma in vitro and in vivo. PLoS One. 2015; 10(8):e0135265. PMC: 4530866. DOI: 10.1371/journal.pone.0135265. View

Horn S, Figl A, Rachakonda P, Fischer C, Sucker A, Gast A . TERT promoter mutations in familial and sporadic melanoma. Science. 2013; 339(6122):959-61. DOI: 10.1126/science.1230062. View

Shay J, Bacchetti S . A survey of telomerase activity in human cancer. Eur J Cancer. 1997; 33(5):787-91. DOI: 10.1016/S0959-8049(97)00062-2. View

Hannen R, Bartsch J . Essential roles of telomerase reverse transcriptase hTERT in cancer stemness and metastasis. FEBS Lett. 2018; 592(12):2023-2031. DOI: 10.1002/1873-3468.13084. View

Gomez D, Armando R, Cerrudo C, Ghiringhelli P, Gomez D . Telomerase as a Cancer Target. Development of New Molecules. Curr Top Med Chem. 2016; 16(22):2432-40. PMC: 4997958. DOI: 10.2174/1568026616666160212122425. View

Jafri M, Ansari S, Alqahtani M, Shay J . Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med. 2016; 8(1):69. PMC: 4915101. DOI: 10.1186/s13073-016-0324-x. View

Zhou N, Fei D, Zong S, Zhang M, Yue Y . MicroRNA-138 inhibits proliferation, migration and invasion through targeting hTERT in cervical cancer. Oncol Lett. 2016; 12(5):3633-3639. PMC: 5104143. DOI: 10.3892/ol.2016.5038. View

Puri N, Pitman R, Mulnix R, Erickson T, Iness A, Vitali C . Non-small cell lung cancer is susceptible to induction of DNA damage responses and inhibition of angiogenesis by telomere overhang oligonucleotides. Cancer Lett. 2013; 343(1):14-23. PMC: 5839143. DOI: 10.1016/j.canlet.2013.09.010. View

Nguyen D, Chang S . Development of Novel Therapeutic Agents by Inhibition of Oncogenic MicroRNAs. Int J Mol Sci. 2017; 19(1). PMC: 5796015. DOI: 10.3390/ijms19010065. View

10.

Huang F, Hodis E, Xu M, Kryukov G, Chin L, Garraway L . Highly recurrent TERT promoter mutations in human melanoma. Science. 2013; 339(6122):957-9. PMC: 4423787. DOI: 10.1126/science.1229259. View

11.

Guo Z, Maki M, Ding R, Yang Y, Zhang B, Xiong L . Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci Rep. 2014; 4:5150. PMC: 5381490. DOI: 10.1038/srep05150. View

12.

Thomas J, Hergenrother P . Targeting RNA with small molecules. Chem Rev. 2008; 108(4):1171-224. DOI: 10.1021/cr0681546. View

13.

Bianchi F, Nicassio F, Marzi M, Belloni E, DallOlio V, Bernard L . A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer. EMBO Mol Med. 2011; 3(8):495-503. PMC: 3377091. DOI: 10.1002/emmm.201100154. View

14.

Tian X, Dai S, Sun J, Jiang S, Sui C, Meng F . Bufalin Induces Mitochondria-Dependent Apoptosis in Pancreatic and Oral Cancer Cells by Downregulating hTERT Expression via Activation of the JNK/p38 Pathway. Evid Based Complement Alternat Med. 2016; 2015:546210. PMC: 4689913. DOI: 10.1155/2015/546210. View

15.

Folini M, Brambilla C, Villa R, Gandellini P, Vignati S, Paduano F . Antisense oligonucleotide-mediated inhibition of hTERT, but not hTERC, induces rapid cell growth decline and apoptosis in the absence of telomere shortening in human prostate cancer cells. Eur J Cancer. 2005; 41(4):624-34. DOI: 10.1016/j.ejca.2004.12.002. View

16.

Sullivan H, Readmond C, Radicella C, Persad V, Fasano T, Wu C . Binding of Telomestatin, TMPyP4, BSU6037, and BRACO19 to a Telomeric G-Quadruplex-Duplex Hybrid Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent. ACS Omega. 2018; 3(11):14788-14806. PMC: 6289566. DOI: 10.1021/acsomega.8b01574. View

17.

Shen L, Chen X, Zhang Y . MicroRNA-128 promotes proliferation in osteosarcoma cells by downregulating PTEN. Tumour Biol. 2013; 35(3):2069-74. DOI: 10.1007/s13277-013-1274-1. View

18.

Zhang B, Pan X, Cobb G, Anderson T . microRNAs as oncogenes and tumor suppressors. Dev Biol. 2006; 302(1):1-12. DOI: 10.1016/j.ydbio.2006.08.028. View

19.

Besnard E, Babled A, Lapasset L, Milhavet O, Parrinello H, Dantec C . Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs. Nat Struct Mol Biol. 2012; 19(8):837-44. DOI: 10.1038/nsmb.2339. View

20.

Song G, Wang R, Guo J, Liu X, Wang F, Qi Y . miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively. Sci Rep. 2015; 5:15793. PMC: 4623477. DOI: 10.1038/srep15793. View