Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation.
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.
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.|Department of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.|Present address: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
Mark Borris D
MB
Aldonza
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Ji-Young
JY
Hong
Center for Food and Bioconvergence, College of Agriculture and Life Sciences, Seoul National University, Seoul 151-742, Korea.
Malona V
MV
Alinsug
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Jayoung
J
Song
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Sang Kook
SK
Lee
D000072283:A549 Cells; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation; D005472:Fluorouracil / Q000494:pharmacology; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008745:Methylation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D004317:Doxorubicin; D005472:Fluorouracil; D000071316:Forkhead Box Protein O3; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014404:Tubulin; C513055:ABCB1 protein, human; C499517:FOXO3 protein, human; C498585:TUBB3 protein, human; C421109:multidrug resistance-associated protein 1
ABCB1; FOXO3a; TUBB3; multidrug resistance; paclitaxel resistance