Číslo abstraktu: p11
Classical taxanes are widely used cytostatics in treatment of a broad range of solid tumors. However, their clinical use is limited by the development of resistance, which is one of main obstacles in successful therapy. The role of proteins whose level is changed in paclitaxel resistant cells, can significantly contribute to knowledge of mechanisms of acquired resistance. From parental sensitive cells, we successfully derived MCF7/PAC-RES breast cancer cell subline able to proliferate in 300nM paclitaxel that induced cell death in sensitive cells.
We found several proteins whose expression were significantly downregulated or upregulated in MCF7/PAC-RES. Together with ABCB1 transporter (P-glycoprotein), TRIP6 (thyroid hormone receptor interactor 6) was the most upregulated protein (650%). TRIP6 is LIM-domain containing adaptor protein with known role in many different cellular processes such as actin cytoskeleton reorganization, focal adhesion assembly and telomere protection. TRIP6 also regulates lysophosphatidic acid (LPA)-induced antiapoptotic effects and antagonizes Fas/CD95-initiated apoptosis.
Results and conclusions
We investigated the effect of TRIP6 downregulation in paclitaxel resistant MCF7/PAC-RES and overexpression of TRIP6 in paclitaxel sensitive MCF7 breast cancer cells. Knock-down of TRIP6 in paclitaxel resistant MCF7 breast cancer cells significantly decreased cell viability when incubated with 300 nM paclitaxel. Surprisingly, overexpression of ectopic FLAG tagged TRIP6 in paclitaxel sensitive MCF7 cells does not protect cells against apoptosis when incubated with 300 nM paclitaxel. TRIP6 has ability to shuttle between nucleus and cytosol, however, in both paclitaxel sensitive and paclitaxel resistant MCF7 cells, TRIP6 localizes only in cytosol. We conclude TRIP6 can contribute to paclitaxel resistance together with high P-glycoprotein expression in MCF7/PAC-RES breast cancer cells.
This work was supported by research project PRVOUK P27 from the Charles University in Prague and by grant NT 13679-4 from the Internal Grant Agency, Ministry of Health of the Czech Republic.
Datum přednesení příspěvku: 2. 12. 2015