Article

The two faces of FBW7 in cancer drug resistance.

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
BioEssays (Impact Factor: 4.84). 11/2011; 33(11):851-9. DOI: 10.1002/bies.201100101
Source: PubMed

ABSTRACT Chemotherapy is an important therapeutic approach for cancer treatment. However, drug resistance is an obstacle that often impairs the successful use of chemotherapies. Therefore, overcoming drug resistance would lead to better therapeutic outcomes for cancer patients. Recently, studies by our own and other groups have demonstrated that there is an intimate correlation between the loss of the F-box and WD repeat domain-containing 7 (FBW7) tumor suppressor and the incurring drug resistance. While loss of FBW7 sensitizes cancer cells to certain drugs, FBW7-/- cells are more resistant to other types of chemotherapies. FBW7 exerts its tumor suppressor function by promoting the degradation of various oncoproteins that regulate many cellular processes, including cell cycle progression, cellular metabolism, differentiation, and apoptosis. Since loss of the FBW7 tumor suppressor is linked to drug resistance, FBW7 may represent a novel therapeutic target to increase drug sensitivity of cancer cells to conventional chemotherapeutics. This paper thus focuses on the new functional aspects of FBW7 in drug resistance.

0 Bookmarks
 · 
244 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c- Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anti-cancer therapeutic strategy.
    Oncotarget 04/2014; 5(8):2000-2015. · 6.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: F-box/WD repeat-containing protein 7 (FBW7) is a member of the F-box protein family that regulates cell cycle progression and cell growth and differentiation. FBW7 also functions as a tumor suppressor. A cisplatin (CDDP)-based multidrug chemotherapy regimen is standard for nasopharyngeal carcinoma (NPC), but drug resistance is an increasing problem. Here, we evaluated the relationship between FBW7 and multidrug resistance-associated protein (MRP), and its correlation with drug resistance in NPC, and explored the mechanism underlying drug resistance to CDDP in this disease. We used cell viability assays, Western blotting, and small interfering RNA (siRNA) interference to investigate the underlying mechanism underlying CDDP resistance in a NPC cell line. The expression of FBW7 and MRP was detected by Western blotting after siRNA interference in the CDDP-resistant NPC cell line, CNE2-CDDP. The 3-(4 5-dimethyl-2-thiazolyl)-2 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to evaluate drug sensitivity of various types of antitumor drugs, including paclitaxel (PCX), CDDP, fluorouracil (5-FU), and vincristine (VCR). We found that siRNA-mediated upregulation of FBW7 significantly increased CDDP chemosensitivity. The IC50 values of CDDP in siRNA-FBW7-CNE2-CDDP and FBW7-CNE2-CDDP-NC cells were 2.485 ± 0.155 and 4.867 ± 0.442 μmol/mL, respectively. The IC50 values of PCX, CDDP, 5-FU, and VCR were significantly decreased in siRNA-FBW7-CNE2 than in FBW7-CNE2-NC (3.46 ± 0.14 vs. 46.21 ± 6.03 μmol/mL; 3.76 ± 0.54 vs. 39.45 ± 0.96 μmol/mL; 2.14 ± 1.67 vs. 28.76 ± 1.89 μmol/mL; 4.43 ± 0.89 vs. 87.90 ± 3.45 μmol/mL, respectively). The IC50 of CDDP was significantly less in siRNA-FBW7-CNE2-CDDP than in FBW7-CNE2-CDDP-NC. The level of FBW7 expression in CNE2 cells was correlated with CDDP chemosensitivity. siRNA-mediated upregulation of FBW7 expression downregulated the expression of MRP, significantly increasing drug sensitivity in CNE2 cells.
    Tumor Biology 01/2015; · 2.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ampelopsin (AMP), a plant flavonoid, has been reported to inhibit cell growth and/or induce apoptosis in various types of tumor. The aim of the present study was to assess the apoptosis‑inducing activity of AMP in A549 human lung adenocarcinoma epithelial cells and the associated underlying mechanism. A549 cells were incubated with different concentrations of AMP in culture medium. Cell growth and apoptosis were evaluated by MTT assay and Annexin V/propidium iodide double staining and flow cytometry, respectively. In addition, western blotting and reverse transcription quantitative polymerase chain reaction analysis were used to examine the time-dependent changes in protein expression. Certain changes in apoptotic protein expression were detected following exposure to AMP, including X‑linked inhibitor of apoptosis protein release, reduced B‑cell lymphoma 2, myeloid cell leukemia 1 and survivin expression levels, increased Bcl‑2‑associated X protein expression levels and cleaved‑poly ADP ribose polymerase expression. The results revealed that AMP was a potent inhibitor of A549 cell proliferation. The c‑Myc/S‑phase kinase‑associated protein 2 (Skp2) and histone deacetylase (HDAC)1/2 pathways were found to exert an important role in AMP‑induced A549 cell apoptosis, as increased levels of c‑Myc mRNA and reduced levels of c‑Myc/Skp2 and HDAC1 and 2 proteins following AMP treatment were observed. The levels of F‑box and WD repeat‑containing protein 7α (Fbw7α), Fbw7β, Fbw7γ, phosphorylated‑(p‑)c‑Myc (Thr58) and glycogen synthase kinase 3β (GSK3β) proteins involved in c‑Myc ubiquitin‑dependent degradation were also analyzed. Following exposure to AMP, the expression levels of Fbw7α, Fbw7γ and GSK3β were reduced and p‑c‑Myc (Thr58) expression levels were increased. The results suggest that AMP exerts an anticancer effect, which is associated with the degradation of c‑Myc, Skp2 and HDAC1 and 2. The ability of AMP to induce apoptosis independently of Fbwα and Fbw7γ suggests a possible use in drug‑resistant cancer associated with Fbw7 deficiency. Understanding the exact underlying mechanism requires further investigation of the association between c‑Myc and Fbw7α/γ reversal, and analysis of whether Thr58 phosphorylation of c‑Myc is dependent on GSK3β.
    Molecular Medicine Reports 10/2014; · 1.48 Impact Factor

Full-text (2 Sources)

Download
58 Downloads
Available from
May 16, 2014