Table 1.
Contributions of forkhead box (FOX) proteins to drug resistance of cancer cells.
| FOX Members | Model/Cell Type | Corresponding Drug | Function | Ref |
|---|---|---|---|---|
| FOXM1 | Non-small cell lung cancer (NSCLC) patients | Tyrosine kinase inhibitor (TKI) | Contributes to TKI-resistant NSCLC cells Associated with unfavorable prognosis in NSCLC patients |
[123] |
| Ovarian cancer patients | Platinum | Overexpressed in ovarian cancer cell lines and cancer cells in patients’ ascites Targeting FOXM1 improves the cytotoxicity of paclitaxel and cisplatinum in platinum-resistant ovarian cancer |
[124] | |
| Lung adenocarcinoma | Gefitinib | FOXM1 stimulates acquired resistance to gefitinib in lung adenocarcinoma cells through a MET/Akt-dependent positive feedback loop | [125] | |
| Leukemia patient samples | Chemoresistance | Nuclear FOXM1 contributes to chemoresistance in acute myeloid leukemia (AML) FOXM1 inactivation causes a favorable prognosis and provides fertile ground for strategies to suppress this oncogenic transcription factor in AML |
[126] | |
| Colorectal cancer | 5-Fluorouracil | FOXM1 can evoke 5-fluorouracil resistance depending on ATP binding cassette subfamily C member 10 (ABCC10) | [127] | |
| Glioma cells | Temozolomide | FOXM1-mediated repair gene replication factor 5 promotes temozolomide resistance in glioma cells independent of methylguanine-DNA-methyltransferase activation | [128] | |
| Nasopharyngeal carcinoma cells | Paclitaxel | FOXM1 can contribute to drug efflux and paclitaxel resistance by regulating the gene transcription of ABCC5, one of the ABC transporters | [129] | |
| Ovarian cancer patients | Chemo-resistance | The expression of FOXM1 is highly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients | [130] | |
| Bladder cancer | Chemo-resistance | FOXM1 is proposed to directly active ABC G member 2 to enhance drug resistance and drug efflux activation | [131] | |
| Breast cancer patients | Epirubicin | FOXM1 can target nijmegen breakage syndrome gene to modulate DNA damage-stimulated senescence and epirubicin resistance | [132] | |
| Gastric cancer | Docetaxel | FOXM1 might be a new therapeutic target in docetaxel-resistant gastric cancer and can be used as a marker for predicting patient prognosis and monitoring the response to docetaxel | [133] | |
| Cervical cancer | Chemoresistance | The prolyl isomerase Pin1 can modulate chemoresistance by up-regulating FOXM1 and involvement in the Wnt/β-catenin pathway | [134] | |
| Breast cancer patients | Chemoresistance | Targeting X-linked inhibitor of apoptosis gene (XIAP) and Survivin by FOXM1 may contribute to chemoresistance in breast cancer survivors | [135] | |
| Leukemia | Chemoresistance | FOXM1 is overexpressed in B-acute lymphoblastic leukemia (B-ALL) Inhibition of FOXM1 may sensitize B-ALL cells to chemotherapeutic drugs |
[136] | |
| Breast cancer | Epirubicin | The suppression of ubiquitination and degradation of FOXM1 by ubiquitin thioesterase OTUB1 has been suggested to play a key role in genotoxic agent resistance | [137] | |
| Breast cancer | Paclitaxel | Paclitaxel resistance can be modulated by deregulating FOXM1 expression to regulate kinesin family member 20A in mitotic catastrophe | [138] | |
| Ovarian cancer | Chemoresistance | Overexpression of FOXM1 can enhance the expression and activity of β-catenin in chemoresistant cells, whereas downregulation of FOXM1 may suppress these events | [139] | |
| Gastric cancer | Oxaliplatin | FOXM1-stimulated resistance to oxaliplatin is partially mediated through its target gene Mcl-1 | [140] | |
| Ovarian cancer | Paclitaxel | Upregulation of FOXM1 contributes to paclitaxel resistance by suppressing mitotic catastrophe | [141] | |
| Ovarian cancer | Cisplatin | FOXM1 can contribute to cisplatin sensitivity by modulating exonuclease 1 | [142] | |
| FOXC1 | Breast cancer patients | Endocrine | FOXC1 expression is related to decreased or undetectable estrogen receptor (ER) expression in recurrent tumors FOXC1 is involved in ERα silencing through counteracting GATA binding protein 3 binding and has been implicated in endocrine resistance |
[143] |
| FOXQ1 | Breast cancer | Chemoresistance | Platelet-derived growth factor receptors have been suggested as critical mediators of breast cancer chemoresistance driven by FOXQ1 and have potential implications for investigating novel therapeutic combinations to treat breast cancer | [106] |
| NSCLC | Chemoresistance | Overexpression of FOXQ1 elicits opposing effects on these phenotypes in vivo by regulating epithelial-mesenchymal transition (EMT) and modulating chemosensitivity in NSCLC | [144] | |
| FOXC2 | Ovarian cancer | Cisplatin | FOXC2 stimulates EMT and metastasis in cisplatin-resistant human ovarian cancer cells | [145] |
| FOXC2 promotes the resistance of human ovarian cancer cells to cisplatin by activating the Amkt and MAPK-signaling pathways | [146] | |||
| Nasopharyngeal carcinomas | Chemoresistance | FOXC2 may stimulate chemoresistance through activation of EMT | [147] | |
| FOXD1 | Breast cancer | Chemoresistance | FOXD1 can stimulate breast cancer growth and chemoresistance by modulating p27 | [148] |
| FOXO3a | Lung cancer | Gefitinib | NF-ĸB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance | [149] |
| Colorectal cancer | Cetuximab | FOXO3a contributes to cetuximab resistance in RAS wild-type metastasis through c-Myc | [150] | |
| Multi drug resistance cells | Docetaxel and Paclitaxel | Paclitaxel-resistant cancer cell-derived secretomes escape from apoptosis through FOXO3a-driven glycolytic modulation in association with ABCB1 | [151] | |
| HeLa cells | Cisplatin | Butein may sensitize HeLa cells to cisplatin through the ERK/p38 MAPK and Akt pathways by targeting FOXO3a | [152] | |
| Ovarian cancer | Cisplatin | -8-Bromo-7-methoxychrysin-induced apoptosis in cisplatin-sensitive and -resistant cells can occur through modulation of Akt/FOXO3a | [153] | |
| FOXO1 | Hepatocellular carcinoma | Doxorubicin | Expression of Bim is mediated by FOXO1 and indirectly downregulated by thyroid hormone/hormone receptor, causing chemotherapy resistance and doxorubicin-stimulated metastasis of hepatoma cells | [154] |
| Esophageal squamous cell carcinoma | Chemoresistance | Cancer-associated fibroblasts mediate chemoresistance through a FOXO1/TGFβ signaling loop | [155] | |
| Gastric cancer | Lapatinib | Inactivation of FOXO1 is suggested as a determinant of acquired lapatinib-resistance in HER2-positive breast cancer through upregulation of MET | [156] | |
| Gastric cancer | Cisplatin | FOXO1 may contribute to cisplatin resistance by stimulating the phosphoinositide 3-kinase/Akt pathway | [157] | |
| Leukemia | TKI | Overexpressed FOXO1 can contribute to BCR-ABL1 kinase-independent resistance in chronic myeloid leukemia patients | [158] | |
| NSCLC | TKI | FOXO1 acetylation suppresses cell growth and stimulates apoptosis of NSCLC Posttranslational modifications of FOXO1 modulate EGFR-TKI resistance in NSCLC cells |
[159] | |
| FOXJ2 | Prostate cancer | Castration | The phosphorylation of FOXJ2 is associated with increased expression of NEK6 that can mediate castration resistance in prostate cancer | [160] |
| FOXL2 | Gastric cancer | Chemoresistance | The HMGA2-FOXL2 axis can modulate EMT and metastasis of chemoresistant gastric cancer | [161] |
| FOXP3∆3 | Bladder cancer | Cisplatin | Biased expression of the FOXP3∆3 isoform in aggressive bladder cancer contributes to differentiation and cisplatin chemotherapy resistance | [162] |
| FOXP3 | Lung adenocarcinoma | Cisplatin | Downregulation of FOXP3 can enhance chemosensitivity to cisplatin and suppress cell proliferation in human lung adenocarcinoma | [163] |
| FOXP1 | Gastric cancer | Chemoresistance | FOXP1 may interact with nuclear aurora kinase A, which regulates survivin stability by modulating F-box and leucine rich repeat protein 7 in gastric cancer drug resistance and affects prognosis | [164] |
| Ovarian cancer | Chemoresistance | The expression of nuclear FOXP1 is an independent risk factor related to chemotherapy resistance and the prognosis of patients with ovarian cancer | [165] | |
| FOXA1 | Breast cancer | Tamoxifen | Down-regulation of FOXA1 causes cancer stem cell-like properties in tamoxifen-resistant breast cancer cells through stimulation of interleukin-6 | [166] |
| Prostate cancer | Castrate | FOXA1 modulates androgen receptor variant activity in models of castrate-resistant prostate cancer | [167] | |
| FOXF2 | Breast cancer patients | Multidrug resistance | FOXF2 may contribute to multidrug resistance of basal-like breast cancer by suppressing FOXC2-mediated EMT | [168] |