Mark Borris D Aldonza
Seoul National University, South Korea
Korea Advanced Institute of Science and Technology, South, Korea
Posters & Accepted Abstracts: Immunother Open Acc
Acquired drug resistance is a primary obstacle for effective cancer therapy. The correlation of point mutations in class III �² tubulin (TUBB3) and the prominent overexpression of ATP binding cassette P-glycoprotein (ABCB1), a multidrug resistance gene have been protruding mechanisms of resistance to microtubule disruptors such as paclitaxel (PTX) for many cancers. However, the precise underlying mechanism of the rapid onset of cross resistance to an array of structurally and functionally unrelated drugs in PTX resistant cancers has been poorly understood. We determined that the established PTX resistant cancer cells display ABCB1/ABCC1 associated cross resistance to chemically different drugs such as 5-fluorouracil, docetaxel and cisplatin. We found that feedback activation of TUBB3 can be controlled through the FOXO3a dependent regulation of ABCB1, which resulted in the accentuation of induced PTX resistance and encouraged multiplicity in acquired cross resistance. Regulatory effects of FOXO3a on P-glycoprotein (Pgp) function suggest the involvement of ABCB1 methylation, the ubiquitination of TUBB3, the functional PI3K/Akt pathway and the stimulation of drug induced FOXO3a arginine hyper methylation. In addition, we found that secretome factors from PTX resistant cancer cells with acquired cross resistance support a Pgp association in multidrug resistance (MDR) development, which assisted the FOXO3a mediated control of TUBB3 feedback. The direct silencing of TUBB3 reverses induced multiple cross resistance, reduces drug resistant tumor mass and suppresses the impaired microtubule stability status of PTX resistant cells with transient cross resistance. These findings highlight the control of the TUBB3 response to ABCB1 genetic suppressors as a mechanism to reverse the profuse development of multidrug resistance in cancer.
Email: borris@snu.ac.kr
