Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

Abstract

Persistent activation of Survivin and its overexpression contribute to the formation, progression and metastasis of several different tumor types. Therefore, Survivin is an ideal target for RNA interference mediated-growth inhibition. Blockade of Survivin using specific short hairpin RNAs (shRNA) can significantly reduce prostate tumor growth. RNA interference does not fully ablate target gene expression, owing to the idiosyncrasies associated with shRNAs and their targets. To enhance the therapeutic efficacy of Survivin-specific shRNA, we employed a combinatorial expression of Survivin-specific shRNA and gene associated with retinoid-interferon-induced mortality-19 (GRIM-19). Then, the GRIM-19 coding sequences and Survivin-specific shRNAs were used to create a dual expression plasmid vector and were carried by an attenuated strain of Salmonella enteric serovar typhimurium (S. typhimurium) to treat prostate cancer in vitro and in vivo. We found that the co-expressed Survivin-specific shRNA and GRIM-19 synergistically and more effectively inhibited prostate tumor proliferation and survival, when compared with treatment with either single agent alone in vitro and in vivo. This study has provided a novel cancer gene therapeutic approach for prostate cancer.

Atrazine promotes RM1 prostate cancer cell proliferation by activating STAT3 signaling

“…Activated STAT3 induces the expression of a number of cellular proto-oncogenes, including c-myc, c-fos and c-met, as well as cell cycle regulating proteins such as cyclin D1 and cyclin B1, which are all known to promote tumor growth. Grim-19 directly interacts with STAT3, inhibiting its gene function through Grim-19-depentment inhibitory and stimulatory pathways (34,35). In this study, STAT3 and c-myc were upregulated, and Grim-19 downregulated, indicating that atrazine may upregulate STAT3 by downregulating Grim-19, promoting RM1 cell proliferation.…”

GRIM-19 over-expression represses the proliferation and invasion of orthotopically implanted hepatocarcinoma tumors associated with downregulation of Stat3 signaling

“…Salmonella typhimurium, a type of facultative anaerobic Gram-negative bacteria, can selectively accumulate in solid tumors because of the existence of hypoxic areas within solid tumors (22). Attenuated Salmonella phoPphoQ was used in the current study as a GRIM-19-expressing plasmid carrier because of its potent tumor-targeting ability, low toxicity, and ability to efficiently express exogenous gene products (23). Several studies have indicated that GRIM-19 expressing plasmids in phoPphoQ Salmonella can target solid tumors and be released into implanted tumor cells to successfully over-express GRIM-19 protein.…”

GRIM-19: A master regulator of cytokine induced tumor suppression, metastasis and energy metabolism

“…Acute inflammatory reactions to bacterial presence in tumor microenvironment resulted in tumor lysis (see [154] for a review). GRIM-19 was upregulated during anti-bacterial responses and tumor lysis could be enhanced when such bacteria delivered GRIM-19 expression plasmid to the tumor [155]. However, GRIM-19 was not upregulated in chronic inflammatory conditions like arthritis [156] and IBD [36].…”