Drug-resistance reversal in colorectal cancer cells by destruction of flotillins, the key lipid rafts proteins.

Rok, strany: 2019, 576 - 583

Multi-drug resistance (MDR) of tumor cells attenuates the efficacy of anticancer drugs and has become the main reason for chemotherapy failure. It is indispensable to establish an effective way to reverse multi-drug resistance. Our previous work has shown that down-regulation of the ERK/MAPK signaling pathway activity can reverse the drug-resistance of resistant cells. Further-more, the effect of signal transduction is strongly associated with lipid rafts. The drug-resistance is reversed successfully after lipid rafts are destroyed by heptakis(2, 6-di-O-methyl)-β-cyclodextrin (MβCD). However, the reversal of the drug-resistance is not associated with down-regulation of the expression of ERK1/2. Cell membrane permeability may increase when lipid rafts are destroyed by MβCD, causing the reversal of drug-resistance due to an increase in accumulation of the drugs in the cytoplasm. To minimize the influence of MβCD on the cell membrane structure, we selected flotillin, a marker protein of lipid rafts, as the target molecule, to further investigate the mechanism of changes in drug resistance after destruction of the lipid rafts. The effect of flotillin on the reversal of the drug resistance was examined using an RNA interference (RNAi) in a retrovirus system in human drug-resistant strains of colorectal cancer cell line HCT-15. The results demonstrate that flotillin-1 downregulation by RNAi (Flot1-RNAi) reduced the drug resistance, caused cell cycle arrest and decreased the expression of ERK1/2; however, apoptosis was not significantly affected. Knockdown of flotillin-2 by RNAi (Flot2-RNAi) had effects similar to those of Flot1-RNAi except that the effects on expression of ERK1/2 and apoptosis were different. Screening of multiple pathways indicated that the PI3K/Akt signaling pathway was closely related. This experiment demonstrates the association between PI3K and drug resistance through the activation of PI3K and suggests that PI3K may play a key role during the development of resistance in CRC. The results reveal that the levels of IRS-1 and PI3K proteins in the Flot1-RNAi and Flot2-RNAi groups were significantly down-regulated. Knockdown of flotillins by RNAi reduced the resistance of HCT-15/ADM cells; the results investigations of the Akt pathway indicate a decrease in resistance after lipid raft destruction. These data confirm that knockdown of flotillin reduces the resistance of HCT-15/ADM cells, and the mechanism may be relevant to the PI3K/Akt pathway. Additionally, flotillin may be used as a potential target for chemotherapy in the treatment of colorectal cancer.

ISO 690:

Ye, D., Ye, S., Yu, S., Shu, F., Xu, S., Chen, Q., Wang, Y., Tang, Z., Pan, C. 2019. Drug-resistance reversal in colorectal cancer cells by destruction of flotillins, the key lipid rafts proteins.. In NEOPLASMA, vol. 66, no.4, pp. 576-583. 0028-2685.

APA:

Ye, D., Ye, S., Yu, S., Shu, F., Xu, S., Chen, Q., Wang, Y., Tang, Z., Pan, C. (2019). Drug-resistance reversal in colorectal cancer cells by destruction of flotillins, the key lipid rafts proteins.. NEOPLASMA, 66(4), 576-583. 0028-2685.

Vydavateľ: AEPress, Ltd.