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Progression elevated gene‐3 promoter (PEG‐Prom) confers cancer cell selectivity to human polynucleotide phosphorylase ( hPNPase old‐35 )‐mediated growth suppression
Author(s) -
Chan Isaac,
Lebedeva Irina V.,
Su ZaoZhong,
Sarkar Devanand,
Valerie Kristoffer,
Fisher Paul B.
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21320
Subject(s) - pancreatic cancer , cancer research , biology , cancer , cancer cell , polynucleotide phosphorylase , cell growth , cell cycle , microbiology and biotechnology , growth inhibition , purine nucleoside phosphorylase , biochemistry , genetics , enzyme , purine
Abstract The poor prognosis of pancreatic cancer patients using currently available therapies mandates novel therapeutics that combine anti‐neoplastic potency with toxicity‐minimizing cancer specificity. Employing an overlapping pathway screen to identify genes exhibiting coordinated expression as a consequence of terminal cell differentiation and replicative senescence, we identified human polynucleotide phosphorylase ( hPNPase old‐35 ), a 3′,5′‐exoribonuclease that exhibits robust growth‐suppressing effects in a wide spectrum of human cancers. A limitation to the anti‐neoplastic efficacy of hPNPase old‐35 relates to its lack of cancer specificity. The promoter of Progression Elevated Gene ‐3 (PEG‐Prom), discovered in our laboratory via subtraction hybridization in a transformation progression rodent tumor model functions selectively in a diverse array of human cancer cells, with limited activity in normal cells. An adenovirus constructed with the PEG‐Prom driving expression of hPNPase old‐35 containing a C‐terminal Hemaglutinin (HA)‐tag (Ad.PEG. hPNPase old‐35 ) was shown to induce robust transgene expression, growth suppression, apoptosis, and cell‐cycle arrest in a broad panel of pancreatic cancer cells, with minimal effects in normal immortalized pancreatic cells. hPNPase old‐35 expression correlated with arrest in the G 2 /M phase of the cell cycle and up‐regulation of the cyclin‐dependent kinase inhibitors (CDKI) p21 CIP1/WAF‐1/MDA‐6 and p27 KIP1 . In a nude mouse xenograft model, Ad.PEG. hPNPase old‐35 injections effectively inhibited growth of human pancreatic cancer cells in vivo. These findings support the potential efficacy of combining a cancer‐specific promoter, such as the PEG‐Prom, with a novel anti‐neoplastic agent, such as hPNPase old‐35 , to create a potent, targeted cancer therapeutic, especially for a devastating disease like pancreatic cancer. J. Cell. Physiol. 215: 401–409, 2008. © 2007 Wiley‐Liss, Inc.