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Erschienen in: Journal of Cancer Research and Clinical Oncology 6/2019

23.04.2019 | Original Article – Cancer Research

TPP1 OB-fold domain protein suppresses cell proliferation and induces cell apoptosis by inhibiting telomerase recruitment to telomeres in human lung cancer cells

verfasst von: Jinfang Zhu, Weiran Liu, Chen Chen, Hua Zhang, Dongsheng Yue, Chenguang Li, Lianmin Zhang, Liuwei Gao, Yansong Huo, Chang Liu, Giuseppe Giaccone, Bin Zhang, Changli Wang

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 6/2019

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Abstract

Purpose

Maintaining telomeres by recruiting telomerase-to-chromosome ends is essential for cancer cell survival. Inhibiting telomerase recruitment to telomeres represents a novel strategy for telomere-based lung cancer therapy. However, approaches for interrupting telomerase recruitment for cancer therapy still need to be explored.

Methods

The telomere-binding protein TPP1 is responsible for recruiting telomerase to telomeres and synthesizing telomeres through the association between the oligosaccharide/oligonucleotide-binding (OB)-fold domain of TPP1 and telomerase reverse transcriptase. We overexpressed the TPP1 OB domain (TPP1-OB) by lentivirus infection in lung cancer cells. Telomere length was examined by Southern blot analysis of terminal restriction fragments. The effects of TPP1-OB on cell proliferation, the cell cycle, apoptosis, chemosensitivity, and tumor growth were evaluated in vitro and in vivo.

Result

TPP1-OB inhibited the recruitment of telomerase to telomeres and shortened telomere length by acting as a dominant-negative mutant of TPP1. TPP1-OB resulted in reduced cell proliferation, G1 cell cycle arrest, and increased cell apoptosis in lung cancer cells. Cell apoptosis occurred mainly through the caspase-3-dependent signaling pathway. TPP1-OB also suppressed anchorage-independent growth and tumor growth in vivo. Moreover, we demonstrated that TPP1-OB enhances the sensitivity of lung cancer cells to the chemotherapeutic drug paclitaxel.

Conclusion

Our results suggest that inhibiting TPP1-mediated telomerase recruitment by expressing the TPP1-OB domain is a potential novel strategy for telomere-targeted lung cancer therapy.
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Literatur
Zurück zum Zitat Biroccio A, Gabellini C, Amodei S, Benassi B, Del Bufalo D, Elli R, Antonelli A, D’Incalci M, Zupi G (2003) Telomere dysfunction increases cisplatin and ecteinascidin-743 sensitivity of melanoma cells. Mol Pharmacol 63:632–638CrossRefPubMed Biroccio A, Gabellini C, Amodei S, Benassi B, Del Bufalo D, Elli R, Antonelli A, D’Incalci M, Zupi G (2003) Telomere dysfunction increases cisplatin and ecteinascidin-743 sensitivity of melanoma cells. Mol Pharmacol 63:632–638CrossRefPubMed
Zurück zum Zitat Chen C, Gu PL, Wu J, Chen XY, Niu SS, Sun H, Wu LJ, Li N, Peng JH, Shi SH, Fan CY, Huang M, Wong CCL, Gong QG, Kumar-Sinha C, Zhang RG, Pusztai LJ, Rai R, Chang S, Lei M (2017) Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nat Commun. 8:14929CrossRefPubMedPubMedCentral Chen C, Gu PL, Wu J, Chen XY, Niu SS, Sun H, Wu LJ, Li N, Peng JH, Shi SH, Fan CY, Huang M, Wong CCL, Gong QG, Kumar-Sinha C, Zhang RG, Pusztai LJ, Rai R, Chang S, Lei M (2017) Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nat Commun. 8:14929CrossRefPubMedPubMedCentral
Zurück zum Zitat Grill S, Tesmer VM, Nandakumar J (2018) The N terminus of the OB domain of telomere protein TPP1 is critical for telomerase action. Cell Rep 22(5):1132–1140CrossRefPubMedPubMedCentral Grill S, Tesmer VM, Nandakumar J (2018) The N terminus of the OB domain of telomere protein TPP1 is critical for telomerase action. Cell Rep 22(5):1132–1140CrossRefPubMedPubMedCentral
Zurück zum Zitat Zhang X, Mar V, Zhou W, Harrington L, Robinson MO (1999) Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev 13:2388–2399CrossRefPubMedPubMedCentral Zhang X, Mar V, Zhou W, Harrington L, Robinson MO (1999) Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev 13:2388–2399CrossRefPubMedPubMedCentral
Metadaten
Titel
TPP1 OB-fold domain protein suppresses cell proliferation and induces cell apoptosis by inhibiting telomerase recruitment to telomeres in human lung cancer cells
verfasst von
Jinfang Zhu
Weiran Liu
Chen Chen
Hua Zhang
Dongsheng Yue
Chenguang Li
Lianmin Zhang
Liuwei Gao
Yansong Huo
Chang Liu
Giuseppe Giaccone
Bin Zhang
Changli Wang
Publikationsdatum
23.04.2019
Verlag
Springer Berlin Heidelberg
Erschienen in
Journal of Cancer Research and Clinical Oncology / Ausgabe 6/2019
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-019-02921-3

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