Research Papers:

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

Mark Borris D. Aldonza, Ji-Young Hong, Malona V. Alinsug, Jayoung Song and Sang Kook Lee _

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Oncotarget. 2016; 7:34395-34419. https://doi.org/10.18632/oncotarget.9118

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Mark Borris D. Aldonza1,2,4, Ji-Young Hong1, Malona V. Alinsug3, Jayoung Song1, Sang Kook Lee1

1College of Pharmacy, Seoul National University, Seoul 151-742, Korea

2Department of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea

3Center for Food and Bioconvergence, College of Agriculture and Life Sciences, Seoul National University, Seoul 151-742, Korea

4Present address: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea

Correspondence to:

Sang Kook Lee, email: [email protected]

Keywords: paclitaxel resistance, multidrug resistance, FOXO3a, TUBB3, ABCB1

Received: February 17, 2016     Accepted: April 11, 2016     Published: April 30, 2016


Acquired drug resistance is a primary obstacle for effective cancer therapy. The correlation of point mutations in class III β-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 our 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 triggered through the FOXO3a-dependent regulation of ABCB1, which resulted in the accentuation of induced PTX resistance and encouraged multiplicity in acquired cross-resistance. FOXO3a-directed regulation of P-glycoprotein (P-gp) function suggests that control of ABCB1 involves methylation-dependent activation. Consistently, transcriptional overexpression or downregulation of FOXO3a directs inhibitor-controlled protease-degradation of TUBB3. The functional PI3K/Akt signaling is tightly responsive to FOXO3a activation alongside doxorubicin treatment, which directs FOXO3a arginine hypermethylation. In addition, we found that secretome factors from PTX-resistant cancer cells with acquired cross-resistance support a P-gp-dependent 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.

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