Phi29 pRNA vector for efficient escort of hammerhead ribozyme targeting survivin in multiple cancer cells

    Authors

    H. Y. Liu; S. C. Guo; R. Roll; J. Li; Z. J. Diao; N. Shao; M. R. Riley; A. M. Cole; J. P. Robinson; N. M. Snead; G. X. Shen;P. X. Guo

    Comments

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    Abbreviated Journal Title

    Cancer Biol. Ther.

    Keywords

    pRNA; bacteriophage phi29; ribozyme; gene therapy; nanomotor; DNA-PACKAGING MOTOR; BACTERIAL-VIRUS PHI29; BACTERIOPHAGE-PHI-29 DNA; CHEMICAL-MODIFICATION; PHAGE PHI-29; IN-VIVO; SEQUENCE REQUIREMENT; POTENTIAL PARTS; HEXAMERIC RNA; VIRAL-RNA; Oncology

    Abstract

    Ribozymes are potential therapeutic agents which suppress specific genes in disease-affected cells. Ribozymes have high substrate cleavage efficiency, yet their medical application has been hindered by RNA degradation, aberrant cell trafficking, or misfolding when fused to a carrier. In this study, we constructed a chimeric ribozyme escorted by the motor pRNA of bacteriophage phi29 to achieve proper folding and enhanced stability. A pRNA molecule contains an interlocking loop domain and a 5'/3' helical domain, which fold independently of one another. When a ribozyme is connected to the helical domain, the chimeric pRNA/ribozyme reorganizes into a circularly permuted form, and the 5'/3' ends are relocated and buried in the original 71'/75' positions. Effective silencing of the anti-apoptotic gene survivin by an appropriately designed chimeric ribozyme, as demonstrated at mRNA and protein levels, led to programmed cell death in various human cancer cell lines, including breast, prostate, cervical, nasopharyngeal, and lung, without causing significant non-specific cytotoxicity. Through the interlocking interaction of right and left loops, monomer pRNA/ribozyme chimeras can be incorporated into multi-functional dimer, trimer and hexamer complexes for specific gene delivery. Using the phi29 motor pRNA as an escort may revive the ribozyme's strength in medical application.

    Journal Title

    Cancer Biology & Therapy

    Volume

    6

    Issue/Number

    5

    Publication Date

    1-1-2007

    Document Type

    Article

    Language

    English

    First Page

    697

    Last Page

    704

    WOS Identifier

    WOS:000248259900023

    ISSN

    1538-4047

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