Supplementary Materialsoncotarget-07-34395-s001. is much work remaining to elucidate the precise mechanisms alpha-Bisabolol of action. A rapidly growing paradigm is that targeted therapies require factors that can overcome the spontaneous mutations in -tubulin isotypes to reverse resistance to PTX and other alpha-Bisabolol taxanes [8]. Therefore, designing small molecule drugs and testing rationale drug combinations that can target specific -tubulin isotype modifications to reverse GAQ P-gp-mediated resistance are warranted; however, this is very challenging because alpha-Bisabolol structurally, the seven isotypes of -tubulin have complex differential functional mechanisms on mt and play key roles in cellular homeostasis [9]. Therefore, the discovery of genes that can regulate the feedback control of -tubulin isotypes associated with drug sensitivity is necessary to provide a rationale platform for both MDR biomarkers and therapeutic discoveries. Forkhead box class O (FOXO) transcription factors such as have recently been identified as key players in the initiation of cancer and the development of drug resistance. The anticancer drug-mediated up-regulation of enhances expression, which may directly contribute to the genesis of MDR in general and to the implicated activation-mediated alpha-Bisabolol chemotherapy response, including those cytostatic and cytotoxic effects amended by PTX, DCT, cisplatin (CIS), gefitinib (GEF), and 5-fluorouracil (5-FU) [10, 11]. Identified as downstream targets of the PI3K/Akt pathway, transcription factors are associated with tumorigenesis and chemotherapeutic resistance in several ways, such as through inhibiting the transactivation of drug-target genes (e.g., p27/Kip1, Bcl-xL, cyclin D, and Bim) involved in cell proliferation, apoptosis, and differentiation [12]. In addition, because the overexpression of Akt can increase resistance to PTX, FOXO transcription factors have since been implicated in determining drug sensitivity and affecting other signal transduction pathways that regulate the response to PTX. Similarly, the MAPK member JNK, specifically its sub-members JNK1 and JNK2, augment protection from the toxic effects of PTX [13, 14]. Furthermore, PTX not only induces FOXO3a expression but also enhances its nuclear translocation through a JNK-dependent mechanism and affects its ubiquitin-mediated degradation. Meanwhile, have been observed to compete in binding to similar DNA sequences, which often results in antagonized transcriptional output that has recently been related to genotoxic drug resistance and the response of various cancers to chemotherapy [17, 18]. Considerable progress has been made in determining the mechanism of FOXO-regulated mt organization. Very recently, FOXO has also been implicated in drug-mediated cytoskeletal stress because of its effects on neuronal mt organization following pharmacological damage, which requires Akt kinase [19, 20]. Importantly, some FOXO transcription factors also influence the PTX-induced inhibition of the androgen receptor (AR), suggesting a connection between the mt-dependent trafficking of the AR and the clinical efficacy of PTX as well as that of other taxanes [21]. Although these distinct drug-induced mt organization regulatory events may suggest a connection between -tubulin isotypes such as and FOXO transcription factors, very little is known about the systemic relation of these factors and their collective function as interacting elements in the regulation of the response of cancers to chemotherapeutic drugs and the malignant progression of tumors caused by MDR that often leads to cancer recurrence. Herein, in light of the increasing demand to uncover drug resistance mechanisms, we dissected the function of in regulating feedback in the context of the development of multiple cross-resistance to chemically unrelated cancer chemotherapeutics in PTX-resistant cancer cells, and we extended this event to systemic drug-resistant tumor progression. RESULTS and expression Given the previous reports that separately associate drug-induced FOXO3a phosphorylation and alterations with the overexpression of [5, 11], we sought to examine the transcription and protein expression patterns of and in a panel of non-tumor (normal cell), drug-sensitive cancer, and drug-resistant cancer cell models to correlate their expression with MDR development. A gene expression analysis showed that both and mRNA levels are relatively lower in non-cancer RWPE-1.