Extranodal, nasal-type natural killer (NK)/T-cell lymphoma (NKCL) is an aggressive malignancy with poor prognosis in which, usually, signal transducer and activator of transcription 3 (STAT3) is constitutively activated and oncogenic. Here, we demonstrate that STAT3 activation mostly results from constitutive Janus kinase (JAK)3 phosphorylation on tyrosine 980, as observed in three of the four tested NKCL cell lines and in 20 of the 23 NKCL tumor samples under study. In one of the cell lines and in 4 of 19 (21%) NKCL primary tumor samples, constitutive JAK3 activation was related to an acquired mutation (A573V or V722I) in the JAK3 pseudokinase domain. We then show that constitutive activation of the JAK3/STAT3 pathway has a major role in NKCL cell growth and survival and in the invasive phenotype. Indeed, NKCL cell growth was slowed down in vitro by targeting JAK3 with chemical inhibitors or small-interfering RNAs. In a human NKCL xenograft mouse model, tumor growth was significantly delayed by the JAK3 inhibitor CP-690550. Altogether, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of NKCL that deserves to be tested as a therapeutic target.
The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates in pathogenesis is unclear. Here, we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4high from CXCR4neg/low AML patients. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOD/Shi-scid/IL-2Rγnull (NOG) leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to chemokine CXC motif ligand 12 (CXCL12). Functional analysis showed a greater mobilization of leukemic cells and LICs in response to drugs, suggesting that they target the interaction between leukemic cells and their supportive bone marrow microenvironment. In addition, increased apoptosis of leukemic cells in vitro and in vivo was observed. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs.
In an earlier study we showed that C10ORF97 (chromosome-10, open reading frame-97) was expressed in almost all of the tissues and cell lines tested, and that it inhibited the growth of seven tumor cell lines, including two lung carcinoma cell lines (A549 and PG). Here, we show that C10ORF97 is downregulated in non-small-cell lung cancer (NSCLC) tissue compared with normal lung tissue. Overexpression of C10ORF97 significantly suppressed human lung carcinoma A549 cell growth (proliferation and anchorage-independent growth in soft agar) and motility (migration and adhesion). This tumor-suppressive function of C10ORF97 was also verified in vivo. We further found that C10ORF97 caused G 1 arrest of A549 cells and modulated the expression level of several cell-cycle regulators (such as CDK2, cyclin-E and p27). These effects of C10ORF97 were mediated by physical association between C10ORF97 and Jun-activating domain-binding protein-1 (JAB1), and blocking of JAB1-mediated translocation of p27 from the nucleus to the cytoplasm. Together, these results indicated that C10ORF97 functions as a novel tumor suppressor by modulating several key G 1 /S-regulatory proteins by interacting with JAB1. These findings led us to hypothesize that a single-nucleotide polymorphism (SNP) in the C10ORF97 gene that affects its expression might be associated with susceptibility to NSCLC. SNP216 C4T (rs2297882) in the C10ORF97 Kozak sequence was identified, and allele T of SNP216 suppressed C10ORF97 expression in vitro and in vivo. Furthermore, the TT genotype of SNP216 was associated with an increased risk of NSCLC (adjusted odds ratio ¼ 1.73 (95% confidence interval: 1.33-2.25), P ¼ 4.6 Â 10 -5). These data indicated that C10ORF97 is a tumor suppressor of NSCLC progression and C10ORF97-SNP216 may serve as a predictor of NSCLC.
This study aimed to determine the impact of Lactobacillus plantarum PC170 concurrent with antibiotic treatment and/or during the recovery phase after antibiotic treatment on the body weight, faecal bacterial composition, short-chain fatty acids (SCFAs) concentration, and splenic cytokine mRNA expression of mice. Orally administrated ceftriaxone quantitatively and significantly decreased body weight, faecal total bacteria, Akkermansia muciniphila, and Lactobacillus plantarum, and faecal SCFAs concentration. Ceftriaxone treatment also dramatically altered the faecal microbiota with an increased Chao1 index, decreased species diversities and Bacteroidetes, and more Firmicutes and Proteobacteria. After ceftriaxone intervention, these changes all gradually started to recover. However, faecal microbiota diversities were still totally different from control by significantly increased α- and β-diversities. Bacteroidetes all flourished and became dominant during the recovery process. However, mice treated with PC170 both in parallel with and after ceftriaxone treatment encouraged more Bacteroidetes, Verrucomicrobia, and Actinobacteria, and the diversity by which to make faecal microbiota was very much closer to control. Furthermore, the expression of splenic pro-inflammatory cytokine tumour necrosis factor-α mRNA in mice supplemented with PC170 during the recovery phase was significantly lower than natural recovery. These results indicated that antibiotics, such as ceftriaxone, even with short-term intervention, could dramatically damage the structure of gut microbiota and their abilities to produce SCFAs with loss of body weight. Although such damages could be partly recovered with the cessation of antibiotics, the implication of antibiotics to gut microbiota might remain even after antibiotic treatment. The selected strain PC170 might be a potential probiotic because of its contributions in helping the host animal to remodel or stabilise its gut microbiome and enhancing the anti-inflammatory response as protection from the side effects of antibiotic therapy when it was administered in parallel with and after antibiotic treatment.
Background: Activation of the PI3K/mTOR pathway is thought to be involved in resistance to TRAS. BOLERO-3 is a randomized phase 3, double-blind, placebo-controlled, international, clinical trial evaluating the addition of the mTOR inhibitor EVE (5 mg/day) to TRAS plus vinorelbine (25 mg/m2) in patients with HER2+ advanced breast cancer resistant to TRAS and who were previously treated with a taxane. A total of 569 adult women were randomized 1:1 to receive EVE (n = 284) or PBO (n = 285). Study treatment represented the 2nd, 3rd, or 4th line of chemotherapy-containing regimen for 83% of patients in the metastatic setting. The primary endpoint, progression-free survival based on local radiologic assessment, was significantly longer in the EVE arm versus PBO (HR = 0.78; P = .0067) at a median follow-up of 20 months. Methods: Study drugs were continued until disease progression or unacceptable toxicity. Incidences of adverse events (AEs) were monitored continuously. Dose modifications and discontinuations were recorded. Results: The median duration of exposure to study treatment was similar across treatment groups: 24.8 weeks for EVE, 25.1 weeks for TRAS, and 24.0 weeks for vinorelbine (EVE arm); and 22.9 weeks for PBO, 24.0 weeks for TRAS, and 23.1 weeks for vinorelbine (PBO arm). The AEs were consistent with known drug-safety profiles. Class-effect AEs with mTOR inhibitors (including stomatitis, rash, noninfectious pneumonitis, and hyperglycemia) were higher in the EVE arm and were mainly grade 1/2. Grade 3 class-effect AEs each occurred in <15% of patients (stomatitis [13%], hyperglycemia [2%], and noninfectious pneumonitis [<1%]). Grade 4 noninfectious pneumonitis (<1%) was uncommon; there were no grade 4 events of stomatitis or hyperglycemia, and no grade 3/4 events of rash. The incidence and grade of hematologic AEs were increased in the EVE arm vs the PBO arm, including all grade neutropenia (81% vs 70%), anemia (49% vs 29%), febrile neutropenia (17% vs 4%) and thrombocytopenia (14% vs 2%); grade 3/4 hematologic AEs included neutropenia (grade 3: 35% vs 32%; grade 4: 38% vs 30%), anemia (grade 3: 17% vs 6%; grade 4: 2% vs <1%), febrile neutropenia (grade 3: 11% vs 3%; grade 4: 5% vs 1%), and thrombocytopenia (grade 3: 3% vs <1%; grade 4: 1% vs 0). The incidences and grades of changes in liver enzymes and hyperlipidemia were similar between arms. Serious AEs were reported in 42% of patients in the EVE arm and 20% of patients in the PBO arm (26% and 6% were attributed to study treatments, respectively). A higher percentage of patients discontinued treatment because of AEs in the EVE arm versus PBO (10% vs 5%). In all, 83% of patients required at least 1 EVE dose interruption and/or reduction; 96% of these were attributed to AEs. There were fewer deaths in the EVE arm (37%) compared with PBO (41%). Conclusions: The safety of the combination of EVE, TRAS, and vinorelbine was considered manageable in this heavily pretreated patient population. Overall, the results from BOLERO-3 demonstrate that EVE can be combined with TRAS and chemotherapy to improve efficacy in TRAS-resistant HER2+ advanced breast cancer previously treated with a taxane. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-03.
Ran (Ras-related nuclear protein) plays several important roles in nucleo-cytoplasmic transport, mitotic spindle formation, nuclear envelope/nuclear pore complex assembly, and other diverse functions in the cytoplasm, as well as in cellular transformation when activated. Unlike other Ras superfamily proteins, Ran contains an auto-inhibitory C-terminal tail, which packs against its G domain and bias Ran towards binding GDP over GTP. The biological importance of this Cterminal tail is not well understood. By disrupting the interaction between the C-terminus and the G domain, we were able to generate Ran mutants that are innately active and potently bind to RanBP1 (Ran Binding Protein 1), nuclear export factor CRM1 and nuclear import factor KPNB1.In contrast to previously reported activated Ran mutants, the C-terminus destabilized mutants are hydrolysis competent in cells, support nuclear transport, and do not form nuclear rim staining. Crystal structures show that one of these C-terminal mutations slightly changes its mode of binding to RanBP1. Finally, a high percentage of Ran C-terminus mutations from cancer patients were found to be destabilizing and hyperactivating, suggesting that Ran Cdestabilization might be an unprecedented cellular transformation mechanism in affected cancers. This study also highlights a new drug design strategy towards treating patients with hyperactivated Ras proteins including K-Ras.
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