Co-transduction of ribosomal protein L23 enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in human gastric cancer

Abstract

Induction of murine double minute 2 (MDM2) expression is thought to be a determinant of resistance to p53 gene therapy for cancer. Previous studies have revealed that ribosomal protein L23 (RPL23) inhibits MDM2-mediated p53 degradation through direct binding to MDM2. In addition, ectopically expressed RPL23 was reported to interact with MDM2 in both the nucleus and cytoplasm, by which RPL23 indirectly inhibited MDM2-p53 binding. Based on the known molecular properties of the RPL23 protein, it was speculated that co-transduction of RPL23 may protect wild‑type p53 protein from MDM2-mediated inactivation and, thus, improve the effect of delivering therapeutic exogenous p53. To test this hypothesis, we constructed a bicistronic adenoviral vector expressing both the RPL23 and p53 genes (Ad-RPL23/p53) and compared its tumor-suppressor activity in human gastric cancer with that of a single gene vector for p53 (Ad-p53). In the in vivo and in vitro experiments, we observed that treatment with Ad-RPL23/p53 resulted in a stronger antitumor response compared to that obtained using Ad-p53. Moreover, the antitumor response of the bicistronic adenovirus was obtained not only in MGC803 cells (endogenous mutant p53) but also in MKN45 cells (endogenous wild‑type p53) which were initially resistant to p53 gene transfer, indicating that co-transduction of RPL23 also expanded the utility of p53 gene therapy. Furthermore, in an orthotopic nude mouse model of human gastric cancer, we found that the survival benefit was greater after Ad-RPL23/p53 treatment than after Ad-p53. Taken together, the data presented here demonstrate that co-transduction of RPL23 enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in models of human gastric cancer and support the use of this strategy for cancer treatment.

GRWD1 regulates ribosomal protein L23 levels via the ubiquitin-proteasome system

“…7C). This finding was consistent with previous reports (Meng et al, 2016;Zhang et al, 2010Zhang et al, , 2013. Interestingly, RPL23-mediated growth suppression was restored by co-expression of GRWD1 (Fig.…”

“…In addition, RPL23 inhibits MDM2 ubiquitin ligase activity. Therefore, RPL23 may act as a tumor suppressor Jin et al, 2004;Meng et al, 2016;Zhang et al, 2010Zhang et al, , 2013. By contrast, our previous study identified GRWD1 as a novel negative regulator of p53 and a potential oncogene .…”

“…RPL5, RPL11 and RPL23 bind to MDM2 simultaneously, forming a heterotetramer within cells . Although knockdown of RPL5 or RPL11, but not RPL23, markedly inhibits Act D-driven p53 induction (Bursac et al, 2012;Nicolas et al, 2016), evidence suggests that RPL23 functions as a tumor suppressor (Meng et al, 2016;Zhang et al, 2010Zhang et al, , 2013. The present data suggest that GRWD1 acts together with the E3 ubiquitin ligase EDD [also known as human (h)HYD or UBR5] and proteolytically regulates RPL23, and that this regulatory mechanism may play a role in p53 downregulation by GRWD1.…”

Viral Vector-Based Melanoma Gene Therapy

“…Adenovirus Ad5 dsDNA Strong immunogenicity Broad host range [37,38] Brain [39] Colon [40,41] Esophaegal [42] Gastric [43] Liver [44] Lung [45] Adeno associated viruses AAV (2,3,5,6,8,9) ssDNA Slow expression onset Chromosomal integration [46][47][48][49] Brain [50] Breast [51] Liver [52,53] Lung [54] Prostate [55] Retinoblastoma [56] Alphaviruses SFV, SIN ssRNA Broad host range low immunogenicity [32] Brain [57] Colon [58] Lung [59] Melanoma [60,61] Osteosarcoma [62] Pancreas [63] Prostate [64] Herpes simplex virus HSV1, HSV dsDNA Broad host range Latent infection [65,66] Brain [67,68] Colon [69] Prostate [70] Sarcoma [71] Skin [72] Reoviruses [76,79,80] Breast [81] Gastric ...…”

Ribosomal Protein L23 Negatively Regulates Cellular Apoptosis via the RPL23/Miz-1/C-Myc Circuit in Higher-Risk Myelodysplastic Syndrome

“…It remains to be investigated whether cellular senescence might be involved in the potential mechanisms resulting in RPL23 overexpression MDS patients or is a subordinate aspect. Interestingly, RPL23 has been reported to functionally inhibit the HDM2 ubiquitin ligase and thereby activate p53, leading to growth inhibition and anti-tumour effects in cases of gastric cancer [27][28][29] . In our RPL23-KD SKM-1 cells, however, decreased RPL23 expression was correlated with the induction of apoptosis, and our western Fig.…”