Abstract
Resistance to cisplatin (DDP) and dose-related toxicity remain two important obstacles in the treatment of prostate cancer (PCa) patients with DDP-based chemotherapy. We have investigated whether the knockdown of hypoxia-inducible factor-1 alpha (HIF-1α) by siRNA could enhance the antitumor activity of DDP, and aimed to determine the underlying mechanisms. Intravenous injection of attenuated Salmonella carrying a HIF-1α siRNA-expressing plasmid was used to knockdown HIF-1α in a PC-3 xenograft model. The in vitro and in vivo effects of HIF-1α siRNA treatment and/or DPP on PCa cell proliferation, apoptosis, glycolysis, and production of reactive oxygen species (ROS) were assessed by examining molecular markers specific to each process. The results demonstrated that the treatment of tumor-bearing mice with attenuated Salmonella carrying the HIF-1α siRNA plasmid greatly enhanced the antitumor effects of low-dose DDP. Further mechanistic studies demonstrated that knockdown of HIF-1α improved the response of PCa cells to DDP by redirecting aerobic glycolysis toward mitochondrial oxidative phosphorylation, leading to cell death through overproduction of ROS. Our findings indicate that DDP-based chemotherapy combined with targeting the HIF-1α-regulated cancer metabolism pathway might be an ideal strategy to treat PCa.
Highlights
Prostate cancer (PCa) has become the most common cancer in men, accounting for 26% of all cancers, and 9% of cancer-related deaths in males[1]
Our results showed that DDP combined with the attenuated Salmonella carrying the HIF-1α-siRNA plasmid had an optimally therapeutic effect on prostate cancer (PCa) when compared to DDP alone in a nude mouse xenograft model
Expression of vascular endothelial growth factor (VEGF) and glucose transporter type 4 (GLUT4), which are regulated by HIF-1α, were significantly increased as determined by quantitative real-time PCR
Summary
Prostate cancer (PCa) has become the most common cancer in men, accounting for 26% of all cancers, and 9% of cancer-related deaths in males[1]. DDP resistance can be overcome by elevating the dosage, high doses of DDP often cause severe side effects such as ototoxicity, nephrotoxicity, peripheral neuropathy, gastrointestinal dysfunction, and myelosuppression These adverse events usually lead to drug discontinuation and limited therapeutic efficacy[5]. Our previous studies have demonstrated that a combination of low-dose DDP with gene therapy expressing tumor protein p53 (p53) and mouse double minute 2 homolog (MDM2) siRNA, delivered by attenuated Salmonella enterica serovar Typhi vaccine strain Ty21a (Salmonella Typhi Ty21a), synergistically inhibited ovarian cancer and PCa growth without damaging normal tissues[22,23,24,25]. We tested our hypothesis that knockdown of HIF-1α by siRNA gene therapy delivered by the attenuated Salmonella Typhi Ty21a is a promising strategy to increase the sensitivity of PCa to DDP from the perspective of targeting cancer-specific metabolism. Few toxic side effects associated with the combination therapy were observed
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