Knockdown of TWIST enhances the cytotoxicity of chemotherapeutic drugs in doxorubicin-resistant HepG2 cells by suppressing MDR1 and EMT

Abstract

The transcription factor twist family bHLH transcription factor 1 (TWIST), which is a member of the basic helix-loop-helix class of proteins, is known to induce epithelial-mesenchymal transition (EMT) and promote cancer metastasis. TWIST has previously been reported to be associated with multidrug resistance (MDR), since its depletion increases drug sensitivity. Although these previous studies have established a strong association between EMT and MDR, the molecular mechanism remains obscure. The present study demonstrated that TWIST protein expression was elevated in liver cancer, and was positively correlated with multidrug resistance protein 1 (MDR1) expression. Conversely, MDR1 was negatively correlated with E‑cadherin expression in liver cancer samples. In addition, the present study indicated that doxorubicin-resistant HepG2 (R‑HepG2) cells acquired an EMT phenotype. TWIST was also more highly expressed in R‑HepG2 cells compared with in parental HepG2 cells. Knockdown of TWIST increased the sensitivity of R‑HepG2 cells to 5-fluroracil, cisplatin and doxorubicin through a reduction in MDR1 expression and drug efflux ability. Furthermore, knockdown of TWIST in R‑HepG2 cells inhibited the migratory ability of cells and suppressed the EMT phenotype. These findings demonstrated that targeting TWIST may be considered a novel strategy to overcome drug resistance in liver cancer.

The immunophenotype of epithelial to mesenchymal transition inducing transcription factors in salivary gland adenoid cystic carcinomas

“…Several authors proved its involvement in tumor invasiveness, metastasis, growth, angiogenesis, and apoptosis inhibition, and even in the maintenance of cancer stem cells and the development of chemotherapy resistance [ 27 , 28 , 29 ]. The prometastatic Twist potential relies on its ability to induce an EMT process in cancer cells by turning-down the expression of epithelial specific markers, especially of the E-cadherin and by upregulating the expression of mesenchymal markers mainly of the N-cadherin [ 29 , 30 , 31 ].…”

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

“…In agreement with previous studies, the present study revealed that Twist knockdown reduced metastasis properties by suppressing CSC-like characteristics, migratory ability and invasiveness in CisR OC cells [ 28 , 113 ]. Twist-deficient CisR OC cells exhibited EMT phenotypic characteristics by increasing E-cadherin and reducing N-cadherin and vimentin expression [ 122 ]. Twist knockdown CisR OC cells exhibited reduced DNA repair capacity and increased ER stress mediated cell death.…”

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

“…In colorectal cancer, SNAIL overexpressing CAFs induced chemoresistance of colon cancer cells to 5-FU and paclitaxel in vitro and in vivo. This resistance was mediated by CAF-derived CCL1 and TGF-β (Li et al, 2018a). Perivascular TGF-β could also promote the survival of carcinoma progenitor cells, by reprogramming glutathione metabolism, thus increasing porgenitor cell drug resistance and cancer recurrence (Oshimori et al, 2015).…”