E-cadherin re-expression: Its potential in combating TRAIL resistance and reversing epithelial-to-mesenchymal transition

Abstract

• The major challenges of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis include TRAIL resistance and Epithelial-to-Mesenchymal Transition (EMT) induction in metastatic cancer cells. • Loss of E-cadherin contributes to TRAIL resistance and promotes EMT. • Conversely, re-expressing E-cadherin emerges as a promising strategy to address TRAIL resistance and prevent EMT induction. • Re-expression of E-cadherin enhances cancer cell sensitivity towards TRAIL by facilitating death-inducing signalling complex (DISC) formation, increasing caspase and poly (ADP-ribose) polymerase-1 (PARP) expression, and improving TRAIL-induced cytotoxicity and cell cycle arrest. • Re-expression of E-cadherin prevents EMT initiation by inhibiting the Wnt/β-catenin pathway, preventing claudin downregulation, and reducing EMT-inducing transcriptional activity. • Interestingly, the inhibition of EMT, which involves the reversal of claudin’s downregulation and inhibition of NF-ĸB activity, aid in improving TRAIL-induced apoptosis. The major limitation of conventional chemotherapy drugs is their lack of specificity for cancer cells. As a selective apoptosis-inducing agent, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as an attractive alternative. However, most of the cancer cells are found to be either intrinsically resistant to the TRAIL protein or may develop resistance after multiple treatments, and TRAIL resistance can induce epithelial-to-mesenchymal transition (EMT) at a later stage, promoting cancer invasion and migration. Interestingly, E-cadherin loss has been linked to TRAIL resistance and initiation of EMT, making E-cadherin re-expression a potential target to overcome these obstacles. Recent research suggests that re-expressing E-cadherin may reduce TRAIL resistance by enhancing TRAIL-induced apoptosis and preventing EMT by modulating EMT signalling factors. This reversal of EMT, can also aid in improving TRAIL-induced apoptosis. Therefore, this review provides remarkable insights into the mechanisms underlying E-cadherin re-expression, clinical implications, and potentiation, as well as the research gaps of E-cadherin re-expression in the current cancer treatment.

Topics & Concepts