Oxaliplatin resistance in colorectal cancer enhances TRAIL sensitivity via death receptor 4 upregulation and lipid raft localization

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer death, and its mortality is associated with metastasis and chemoresistance. We demonstrate that oxaliplatin-resistant CRC cells are sensitized to TRAIL-mediated apoptosis. Oxaliplatin-resistant cells exhibited transcriptional downregulation of caspase-10, but this had minimal effects on TRAIL sensitivity following CRISPR-Cas9 deletion of caspase-10 in parental cells. Sensitization effects in oxaliplatin-resistant cells were found to be a result of increased DR4, as well as significantly enhanced DR4 palmitoylation and translocation into lipid rafts. Raft perturbation via nystatin and resveratrol significantly altered DR4/raft colocalization and TRAIL sensitivity. Blood samples from metastatic CRC patients were treated with TRAIL liposomes, and a 57% reduction of viable circulating tumor cells (CTCs) was observed. Increased DR4/lipid raft colocalization in CTCs was found to correspond with increased oxaliplatin resistance and increased efficacy of TRAIL liposomes. To our knowledge, this is the first study to investigate the role of lipid rafts in primary CTCs.

Piezo1 Mechano-Activation Is Augmented by Resveratrol and Differs between Colorectal Cancer Cells of Primary and Metastatic Origin

“…Resveratrol (RSV) is a polyphenol compound that has been shown to have pleotropic effects on cancer cells, especially through its ability to form tightly packed liquid-ordered domains in the cell membrane [ 33 ]. Resveratrol has the ability to sensitize cancer cells to TRAIL under static conditions but has not been investigated in the context of physiological FSS [ 28 , 34 ]. Additionally, resveratrol predominantly integrates into the plasma membrane within minutes of treating cells [ 35 ].…”

“…Lipid rafts have been shown to facilitate the mechanisms of cancer metastasis by acting as protein scaffolds and receptor oligomerization platforms to augment downstream signal transduction [ 27 ]. While the role of LRs in many forms of signal transduction, including apoptotic death receptor signaling, has been well described [ 28 ], the role of rafts in mechanosensation via ion channels remains elusive. We hypothesize that, similar to cholesterol, the presence of lipid rafts will have an amplifying effect on Piezo1 activation and calcium influx.…”

YTHDF3 Facilitates eIF2AK2 and eIF3A Recruitment on mRNAs to Regulate Translational Processes in Oxaliplatin-Resistant Colorectal Cancer

“…In our study, the target genes we chose are all closely related to these two aspects of OXAR. ATP7A, DYRK1B, and ERCC1 , are highly expressed, whereas SLC22A2, SLC31A1, and TNFRSF10A are reduced in chemotherapy-resistant cancer cells. It is interesting that SLC22A2, SLC31A1, and TNFRSF10A translation can be enhanced by YTHDF3 knockdown (Figure A) but fails to be regulated by eIF2AK2 and eIF3A (Figures D–E, H,I).…”

The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma

“…Fast expanding in the research field of understanding the roles of protein palmitoylation in different types of human malignancies has been achieved in the past decades [39][40][41], however, it was revealed that the linkage between palmitoylation and HCC is relatively weak as compared to other tumor types, e.g. breast cancer, prostate cancer, colorectal cancer, leukemia, melanoma, pancreatic cancer and NSCLC [20,23,[42][43][44][45][46][47][48]. Our current study strengthened the connection that AEG-1, a key driver of HCC, is palmitoylated, which negatively regulates its protein stability via proteasome mediated degradation pathway; inhibiting AEG-1 palmitoylation enhances its binding to SND1 and thus the RISC activity, the latter may downregulate the mRNA level of several tumor suppressors as PTEN/TGFB2 and therefore promotes HCC progression.…”