Delivery of a survivin Promoter-Driven antisense Survivin-Expressing plasmid DNA as a cancer therapeutic

A proof-of-concept study

Kun Yuan Lin, Siao Muk Cheng, Shing Ling Tsai, Ju Ya Tsai, Chun Hui Lin, Chun-Hei Cheung

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Survivin is a member of the inhibitor-of-apoptosis proteins family. It is overexpressed in many different cancer types but not in the differentiated normal tissue. In addition, overexpression of survivin promotes cancer cell survival and induces chemotherapeutic drug resistance, making it an attractive target for new anticancer interventions. Despite survivin being a promising molecular target for anticancer treatment, it is widely accepted that survivin is only a “semi-druggable” target. Therefore, it is important to develop a new strategy to target survivin for anticancer treatment. In this study, we constructed a novel survivin promoter-driven full-length antisense survivin (pSur/AS-Sur) expression plasmid DNA. Promoter activity assay revealed that the activity of the survivin promoter of pSur/AS-Sur correlated with the endogenous expression of survivin at the transcriptional level in the transfected A549, MDA-MB-231, and PANC-1 cancer cells. Western blot analysis showed that liposomal delivery of pSur/AS-Sur successfully downregulated the expression of survivin in A549, MBA-MB-231, and PANC-1 cells in vitro. In addition, delivery of pSur/AS-Sur induced autophagy, caspase-dependent apoptosis, and caspase-independent apoptosis as indicated by the increased LC3B-II conversion, autophagosome formation, caspase-9/-3 and poly(ADP-ribose) polymerase-1 cleavage, and apoptosis-inducing factor nuclear translocation in A549, MBA-MB-231, and PANC-1 cells. Importantly, liposomal delivery of pSur/AS-Sur was also capable of decreasing the proliferation of the survivin/MDR1 coexpressing multidrug-resistant KB-TAX50 cancer cells and the estrogen receptor-positive tamoxifen-resistant MCF7-TamC3 cancer cells in vitro. In conclusion, the results of this study suggest that delivery of a survivin promoter-driven antisense survivin-expressing plasmid DNA is a promising way to target survivin and to treat survivin-expressing cancers in the future.

Original languageEnglish
Pages (from-to)2601-2613
Number of pages13
JournalOncoTargets and Therapy
Volume9
DOIs
Publication statusPublished - 2016 May 3

Fingerprint

Plasmids
DNA
Neoplasms
Caspases
Therapeutics
Apoptosis Inducing Factor
Apoptosis
Inhibitor of Apoptosis Proteins
Caspase 9
Autophagy
Tamoxifen
Drug Resistance
Caspase 3
Estrogen Receptors
Cell Survival
Down-Regulation
Western Blotting
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology (medical)

Cite this

Lin, Kun Yuan ; Cheng, Siao Muk ; Tsai, Shing Ling ; Tsai, Ju Ya ; Lin, Chun Hui ; Cheung, Chun-Hei. / Delivery of a survivin Promoter-Driven antisense Survivin-Expressing plasmid DNA as a cancer therapeutic : A proof-of-concept study. In: OncoTargets and Therapy. 2016 ; Vol. 9. pp. 2601-2613.
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abstract = "Survivin is a member of the inhibitor-of-apoptosis proteins family. It is overexpressed in many different cancer types but not in the differentiated normal tissue. In addition, overexpression of survivin promotes cancer cell survival and induces chemotherapeutic drug resistance, making it an attractive target for new anticancer interventions. Despite survivin being a promising molecular target for anticancer treatment, it is widely accepted that survivin is only a “semi-druggable” target. Therefore, it is important to develop a new strategy to target survivin for anticancer treatment. In this study, we constructed a novel survivin promoter-driven full-length antisense survivin (pSur/AS-Sur) expression plasmid DNA. Promoter activity assay revealed that the activity of the survivin promoter of pSur/AS-Sur correlated with the endogenous expression of survivin at the transcriptional level in the transfected A549, MDA-MB-231, and PANC-1 cancer cells. Western blot analysis showed that liposomal delivery of pSur/AS-Sur successfully downregulated the expression of survivin in A549, MBA-MB-231, and PANC-1 cells in vitro. In addition, delivery of pSur/AS-Sur induced autophagy, caspase-dependent apoptosis, and caspase-independent apoptosis as indicated by the increased LC3B-II conversion, autophagosome formation, caspase-9/-3 and poly(ADP-ribose) polymerase-1 cleavage, and apoptosis-inducing factor nuclear translocation in A549, MBA-MB-231, and PANC-1 cells. Importantly, liposomal delivery of pSur/AS-Sur was also capable of decreasing the proliferation of the survivin/MDR1 coexpressing multidrug-resistant KB-TAX50 cancer cells and the estrogen receptor-positive tamoxifen-resistant MCF7-TamC3 cancer cells in vitro. In conclusion, the results of this study suggest that delivery of a survivin promoter-driven antisense survivin-expressing plasmid DNA is a promising way to target survivin and to treat survivin-expressing cancers in the future.",
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Delivery of a survivin Promoter-Driven antisense Survivin-Expressing plasmid DNA as a cancer therapeutic : A proof-of-concept study. / Lin, Kun Yuan; Cheng, Siao Muk; Tsai, Shing Ling; Tsai, Ju Ya; Lin, Chun Hui; Cheung, Chun-Hei.

In: OncoTargets and Therapy, Vol. 9, 03.05.2016, p. 2601-2613.

Research output: Contribution to journalArticle

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