H-Ras regulation of TRAIL death receptor mediated apoptosis

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through the death receptors (DRs) 4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. Here we provide evidence demonstrating the role of H-Ras in TRAIL receptor mediated apoptosis. By analyzing the genome wide mRNA expression data of the NCI60 cancer cell lines, we found that H-Ras expression was consistently upregulated in TRAIL-resistant cell lines. By contrast, no correlation was found between TRAIL sensitivity and K-Ras expression levels or their mutational profiles. Notably, H-Ras upregulation associated with a surface deficiency of TRAIL death receptors. Selective inhibition of H-Ras activity in TRAIL-resistant cells restored the surface expression of both DR4 and DR5 without changing their total protein levels. The resulting cells became highly susceptible to both TRAIL and agonistic DR5 antibody, whereas K-Ras inhibition had little or no effect on TRAIL-induced apoptosis, indicating H-Ras plays a distinct role in the regulation of TRAIL death receptors. Further studies are warranted to determine the therapeutic potential of H-Ras-specific inhibitors in combination with TRAIL receptor agonists.

Aloperine executes antitumor effects against multiple myeloma through dual apoptotic mechanisms

“…TRAIL interaction with DR4 and DR5 transduces the death receptor (extrinsic) and mitochondrial apoptosis signaling pathways through the activation of caspase-8 and caspase-10; therefore, TRAIL is usually regarded as a drug that treats cancer cells through cFLIP [ 30 , 31 ]. To investigate whether aloperine is a feasible agent to enhance TRAIL sensitivity in MM, we analyzed the cytotoxicity of aloperine in combination with TRAIL in MM cell lines.…”

5‐Fluorouracil preferentially sensitizes mutant KRAS non‐small cell lung carcinoma cells to TRAIL‐induced apoptosis

“…Oncogenic RAS has also been shown to increase DR5 expression to promote TRAIL‐induced apoptosis in lung and oral cancer cell lines (Chen et al., 2013; Oh et al., 2012). Moreover, upregulation of HRAS in cancer cells was shown to be associated with decreased DR4 and DR5 expression, leading to TRAIL resistance (Chen et al., 2014). In our study, we observed an increase in TRAIL sensitivity in mutant KRAS NSCLC cells (Figure 1A), but no correlation between KRAS status and DR4 and DR5 expression was observed (Figure 3A), supporting the previous findings that response to TRAIL in mutant KRAS cells depends on the cell type.…”

Oncogenic Ras suppresses ING4-TDG-Fas axis to promote apoptosis resistance

“…Ectopic TDG expression led to the activation of extrinsic apoptosis through the induction of Fas expression. Interestingly, oncogenic Ras signaling has been shown to inhibit apoptosis by regulating the expression of various players in the apoptosis response [ 30 – 32 ]. As the major death receptor, Fas was downregulated in many cancer cells.…”