Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors in the world. NSCLC shows serious effect on prognosis for drug resistance, and it is necessary to study the molecular mechanism for drug resistance in NSCLC. Ubiquitin-proteasome system (UPS) can regulate some important cellular processes by degrading short-term protein, and the abnormal expression is closely related to the occurrence, development and prognosis of tumor. The F-box family protein is an important component of the ubiquitin proteasome, such as cycle regulation, transcriptional regulation, signal transduction, apoptosis and differentiation. F-box and WD-40 domain protein 7 (FBXW7) is just the classic protein components among F-box family protein. Studies have shown that FBXW7 is related to drug resistance in NSCLC. The main mechanism is that FBXW7 mutation leads to drug resistance by reducing ubiquitination and degradation of its downstream proteins, including Snail protein, myeloid cell leukemia sequence 1 (MCL-1), mammalian target of rapamycin (mTOR), and coiled-coil-domain containing 6 (CCDC6). Rapamycin, histone deacetylase inhibitor MS-275, and rabdosia are effective in drug-resistant NSCLC patients with FBXW7 mutation.
Carcinoma, Non-Small-Cell Lung ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; F-Box-WD Repeat-Containing Protein 7 ; Humans ; Lung Neoplasms

OBJECTIVETo evaluate the expression of FBXW7 in esophageal squamous cell carcinoma (ESCC) and to explore the correlation of FBXW7 expression with clinicopathologic features and prognosis of ESCC.

METHODSNinety cases of ESCC and twenty cases of tumor-adjacent normal tissues and forty intraepithelial neoplasia tissues were detected by immunohistochemistry methods. The expression of FBXW7 in 40 surgical ESCC tissues and tumor-adjacent normal tissues was detected by Western blotting and RT-PCR. The relationship between the expression of FBXW7, clinicopathological characteristics and prognosis was analyzed.

RESULTSThe positive rate of FBXW7 protein was significantly lower in the ESCC and high-grade intraepithelial neoplasia tissues than in the tumor-adjacent normal tissues and low grade intraepithelial neoplasia tissues (40.0% and 33.3% vs. 85.0% and 77.3%, χ² = 21.923, P < 0.001). The FBXW7 protein was down-regulated in ESCC tissues (P < 0.05), whereas the FBXW7 mRNA was down-regulated in ESCC tissues compared with that in the paracancerous tissues. The expression of FBXW7 was significantly correlated with TNM stage, degree of differentiation, invasion depth and lymph node metastasis (χ² =9.643, 14.908, 16.294, 10.222, respectively, P = 0.002, 0.001, 0.000, 0.001). In the ninety patients, the 5-year survival rates of cases with positive and negative expression of FBXW7 protein was 67.6% and 39.3%, respectively (χ² =6.699, P = 0.01).

CONCLUSIONSThe results of this study demonstrate that FBXW7 expression is significantly declined in ESCC and high grade intraepithelial neoplasia tissues, and is closely correlated with poor prognosis of this disease. FBXW7 as a tumor suppressor gene may play an important role in the carcinogenesis, development and metastasis of ESCC. These results suggest that FBXW7 may become a valuable marker for the severity and prognosis in ESCC.

Biomarkers, Tumor ; metabolism ; Blotting, Western ; Carcinoma, Squamous Cell ; diagnosis ; metabolism ; Cell Cycle Proteins ; genetics ; Down-Regulation ; Esophageal Neoplasms ; diagnosis ; metabolism ; F-Box Proteins ; genetics ; F-Box-WD Repeat-Containing Protein 7 ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Neoplasm Staging ; Prognosis ; RNA, Messenger ; Survival Rate ; Ubiquitin-Protein Ligases ; genetics

BACKGROUDF-Box and WD40 domain containing protein 7 gene (FBXW7) is part of the E3 ubiquitin ligase complex that controls the turnover of various proteins including NOTCH1, c-MYC and Cyclin E.

OBJECTIVETo investigate the mutations of FBXW7 gene in adult T-cell acute lymphoblastic leukemia (T-ALL).

METHODSExon 5-12 of FBXW7 were amplified, cloned and sequenced in 54 adult T-ALL patients; the frequency, position and types of FBXW7 mutation were analyzed; the co-existing of mutations with NOTCH1 and their relevant prognostic significance were explored as well.

RESULTSFBXW7 mutations were identified in 11.1% of adult T-ALL patients. A total of 4 types of point mutations (R465H, R465L, R479P and R505C) and 1 deletion/insertion mutation were observed, and all of them located in WD40 domain of FBXW7. In addition, co-existing mutations with NOTCH1 were identified in 83.3% of patients with FBXW7 mutation. Notably, the co-existed NOTCH1 mutations, including 3 point mutations (L1574P, L1596H and L1600P) and 2 deletion/insertion mutations located in HD domain. Furthermore, patients with FBXW7 mutation only had significantly longer overall survival compared with those without mutation (P=0.049).

CONCLUSIONFBXW7 mutations may play an important role in NOTCH1 mediated pathogenesis in T-ALL.

Adult ; Cell Cycle Proteins ; Exons ; F-Box Proteins ; F-Box-WD Repeat-Containing Protein 7 ; Genes, myc ; Humans ; Mutation ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Ubiquitin-Protein Ligases

Animals ; Carcinogenesis ; Cell Cycle Proteins ; genetics ; metabolism ; Cyclin E ; metabolism ; F-Box Proteins ; genetics ; metabolism ; F-Box-WD Repeat-Containing Protein 7 ; Gene Silencing ; Genes, Tumor Suppressor ; Humans ; Mutation ; Myeloid Cell Leukemia Sequence 1 Protein ; metabolism ; Neoplasms ; genetics ; metabolism ; pathology ; Proto-Oncogene Proteins c-myc ; metabolism ; Receptors, Notch ; metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases ; metabolism ; Ubiquitin-Protein Ligases ; genetics ; metabolism