title: Bortezomib-mediated down-regulation of telomerase and disruption of telomere homeostasis contributes to apoptosis of malignant cells.
abstract: Bortezomib inhibits the ubiquitin/proteasome pathway to achieve its anti-cancer effect and its well characterized activity is the NF-κB inhibition through which the anti-apoptotic bcl-2 expression is down-regulated and apoptosis is subsequently induced. However, the downstream molecular targets of bortezomib are still incompletely defined. Because telomere stabilization via activation of telomerase, induction of telomerase reverse transcriptase (hTERT) and appropriate expression of shelterin proteins is essential to cancer development and progression, we investigated the effect of bortezomib on telomere homeostasis/function in malignant cells. The bortezomib treatment of leukemic (HEL) and gastric cancer cells (BGC-823) led to significant inhibition of hTERT and telomerase expression, widespread dysregulation of shelterin protein expression, and telomere shortening, thereby triggering telomere dysfunction and DNA damage. hTERT over-expression attenuated bortezomib-induced telomere shortening, abnormal shelterin expression and telomere dysfunction. Importantly, bortezomib-mediated apoptosis of malignant cells was partially prevented by hTERT over-expression. Mechanistically, hTERT first robustly enhances bcl2 expression and maintains significantly high residual levels of bcl2 even in bortezomib-treated HEL cells. Second, hTERT protects against bortezomib-induced DNA damage. Our findings collectively reveal a profound impact of bortezomib on telomere homeostasis/function. Down-regulation of hTERT expression and telomere dysfunction induced by bortezomib both contribute to its cancer cell killing actions. It is evident from the present study that hTERT can confer resistance of malignant cells to bortezomib-based target cancer therapy, which may have important clinical implications.
authors.affiliation: Central Research Laboratory, Shandong University Second Hospital, Jinan, PR China.|Department of Microbiology, School of Medicine, Shandong University, Jinan, PR China.|Division of Hematology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.|Karolinska Institutet-Shandong University Collaborative Laboratories for Cancer and Stem Cell Research, Jinan, PR China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Ci
authors.affiliation: Division of Hematology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Bingnan
authors.initials: B
authors.lastname: Li
authors.affiliation: Central Research Laboratory, Shandong University Second Hospital, Jinan, PR China.|Department of Microbiology, School of Medicine, Shandong University, Jinan, PR China.|Karolinska Institutet-Shandong University Collaborative Laboratories for Cancer and Stem Cell Research, Jinan, PR China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Ma
authors.affiliation: Central Research Laboratory, Shandong University Second Hospital, Jinan, PR China.|Karolinska Institutet-Shandong University Collaborative Laboratories for Cancer and Stem Cell Research, Jinan, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Kong
authors.affiliation: Karolinska Institutet-Shandong University Collaborative Laboratories for Cancer and Stem Cell Research, Jinan, PR China.|Department of Hematology, Shandong University Second Hospital, Jinan, PR China.
authors.forename: Chengyun
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Division of Hematology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.|Karolinska Institutet-Shandong University Collaborative Laboratories for Cancer and Stem Cell Research, Jinan, PR China.
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.affiliation: Department of Microbiology, School of Medicine, Shandong University, Jinan, PR China.|Karolinska Institutet-Shandong University Collaborative Laboratories for Cancer and Stem Cell Research, Jinan, PR China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Jia
authors.affiliation: Division of Hematology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.|Karolinska Institutet-Shandong University Collaborative Laboratories for Cancer and Stem Cell Research, Jinan, PR China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000187:drug effects*; D059506:Telomere Shortening / Q000187:drug effects; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D000069286:Bortezomib; C509186:TERT protein, human; D019098:Telomerase
keywords: BCL2; apoptosis; bortezomib; hTERT; telomerase