Inhibition of Pol I Transcription a New Chance in the Fight Against Cancer

While new cancer treatments continue to improve patient outcomes, for some cancers there have been limited or no improvements for a long time. It is for these cases radically new approaches are required. Recent publications proposing ribosome biogenesis, in particular RNA polymerase I transcription, as a suitable target for cancer treatment has been gaining momentum. For example, we demonstrated that CX-5461, a specific RNA polymerase I transcription inhibitor, is effective in treating an aggressive subtype of acute myeloid leukemia, regardless of p53 status. Notably, CX-5461 reduces the leukemia initiating/stem cells, the cell population believed to be responsible for chemotherapy resistance and disease relapse in numerous cancers. Targeting ribosome biogenesis, once considered merely a “housekeeping process,” is showing promise in a continuously growing list of cancers including lymphoma, prostate, and now acute myeloid leukemia. Evidence suggests the therapeutic efficacy of RNA polymerase I therapy in preclinical models is mediated through a variety of mechanisms including nucleolar stress activation of p53, DNA damage-like activation of ataxia-telangiectasia mutated/ataxia-telangiectasia and Rad3 related, and cellular differentiation. Overall, the available data suggests the potential for targeting ribosome biogenesis to be effective in a broad spectrum of cancers. The outcomes of 2 phase 1/2 trials of CX-5461 in hematological malignancies and breast cancer are eagerly awaited.This work was supported by project grants from the National Health and Medical Research Council program grant (#1053792), and the Cancer Council of Victoria grant-in-aid (#1084545)

Ro 31-6045, the inactive analogue of the protein kinase C inhibitor Ro 31-8220, blocks in vivo activation of p70s6k/p85s6k: implications for the analysis of S6K signalling

AbstractThe mitogen-stimulated protein kinase p70s6k/p85s6k (S6K) plays an essential role in cell proliferation and growth, with inhibitors of the S6K signalling pathway showing promise as anti-tumour therapeutics. Here, we report that the bisindolylmaleimide derivative Ro 31-6045, previously reported to be inactive as a kinase inhibitor, inhibited S6K activity in vivo with an IC50=8 μM. Structure/function analysis using mutant forms of S6K indicates that Ro 31-6045 inhibition is independent of the upstream activator mTOR. Ro 31-6045 will prove useful in elucidating the complex activation mechanism of S6K and its independence from mTOR will allow confirmation of functional data obtained using the mTOR inhibitor rapamycin

Relative Expression Levels Rather Than Specific Activity Plays the Major Role in Determining In Vivo AKT Isoform Substrate Specificity

The AKT protooncogene mediates many cellular processes involved in normal development and disease states such as cancer. The three structurally similar isoforms: AKT1, AKT2, and AKT3 exhibit both functional redundancy and isoform-specific functions; however the basis for their differential signalling remains unclear. Here we show that in vitro, purified AKT3 is ∼47-fold more active than AKT1 at phosphorylating peptide and protein substrates. Despite these marked variations in specific activity between the individual isoforms, a comprehensive analysis of phosphorylation of validated AKT substrates indicated only subtle differences in signalling via individual isoforms in vivo. Therefore, we hypothesise, at least in this model system, that relative tissue/cellular abundance, rather than specific activity, plays the dominant role in determining AKT substrate specificity in situ

Familial correlates of adolescent girls' physical activity, television use, dietary intake, weight, and body composition

<p>Abstract</p> <p>Background</p> <p>The family environment offers several opportunities through which to improve adolescents' weight and weight-related behaviors. This study aims to examine the cross-sectional relationships between multiple factors in the family environment and physical activity (PA), television use (TV), soft drink intake, fruit and vegetable (FV) intake, body mass index (BMI), and body composition among a sample of sociodemographically-diverse adolescent girls.</p> <p>Methods</p> <p>Subjects included girls (mean age = 15.7), 71% of whom identified as a racial/ethnic minority, and one of their parents (dyad n = 253). Parents completed surveys assessing factors in the family environment including familial support for adolescents' PA, healthful dietary intake, and limiting TV use; parental modeling of behavior; and resources in the home such as availability of healthful food. Girls' PA and TV use were measured by 3-Day Physical Activity Recall (3DPAR) and dietary intake by survey measures. BMI was measured by study staff, and body fat by dual-energy X-ray absorptiometry (DXA). Hierarchical linear regression models tested individual and mutually-adjusted relationships between family environment factors and girls' outcomes.</p> <p>Results</p> <p>In the individual models, positive associations were observed between family support for PA and girls' total PA (p = .011) and moderate-to-vigorous PA (p=.016), home food availability and girls' soft drink (p < .001) and FV (p < .001) intake, and family meal frequency and girls' FV intake (p = .023). Across the individual and mutually-adjusted models, parental modeling of PA, TV, and soft drink and FV intake was consistently associated with girls' behavior.</p> <p>Conclusions</p> <p>Helping parents improve their physical activity and dietary intake, as well as reduce time watching television, may be an effective way to promote healthful behaviors and weight among adolescent girls.</p

The potential of targeting ribosome biogenesis in high-grade serous ovarian cancer

Overall survival for patients with ovarian cancer (OC) has shown little improvement for decades meaning new therapeutic options are critical. OC comprises multiple histological subtypes, of which the most common and aggressive subtype is high-grade serous ovarian cancer (HGSOC). HGSOC is characterized by genomic structural variations with relatively few recurrent somatic mutations or dominantly acting oncogenes that can be targeted for the development of novel therapies. However, deregulation of pathways controlling homologous recombination (HR) and ribosome biogenesis has been observed in a high proportion of HGSOC, raising the possibility that targeting these basic cellular processes may provide improved patient outcomes. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has been approved to treat women with defects in HR due to germline BRCA mutations. Recent evidence demonstrated the efficacy of targeting ribosome biogenesis with the specific inhibitor of ribosomal RNA synthesis, CX-5461 in v-myc avian myelocytomatosis viral oncogene homolog (MYC)-driven haematological and prostate cancers. CX-5461 has now progressed to a phase I clinical trial in patients with haematological malignancies and phase I/II trial in breast cancer. Here we review the currently available targeted therapies for HGSOC and discuss the potential of targeting ribosome biogenesis as a novel therapeutic approach against HGSOC.This work was supported by the National Health and Medical Research Council (NHMRC) of Australia, project grants (#1043884, 251608, 566702, 166908, 251688, 509087, 400116, 400120, 566876) and a NHMRC Program Grant (#1053792). Cancer Council Victoria research grant (#1065118). Ross D. Hannan and Richard B. Pearson were funded by NHMRC Fellowships

UBF levels determine the number of active ribosomal RNA genes in mammals

In mammals, the mechanisms regulating the number of active copies of the ∼200 ribosomal RNA (rRNA) genes transcribed by RNA polymerase I are unclear. We demonstrate that depletion of the transcription factor upstream binding factor (UBF) leads to the stable and reversible methylation-independent silencing of rRNA genes by promoting histone H1–induced assembly of transcriptionally inactive chromatin. Chromatin remodeling is abrogated by the mutation of an extracellular signal-regulated kinase site within the high mobility group box 1 domain of UBF1, which is required for its ability to bend and loop DNA in vitro. Surprisingly, rRNA gene silencing does not reduce net rRNA synthesis as transcription from remaining active genes is increased. We also show that the active rRNA gene pool is not static but decreases during differentiation, correlating with diminished UBF expression. Thus, UBF1 levels regulate active rRNA gene chromatin during growth and differentiation

‘It's a part of me, I feel naked without it': choice, agency and identity for Muslim women who wear the niqab

In the context of heightened suspicion and anti-Muslim stereotypes in a post-9/11 and 7/7 era, Muslim women who wear the niqab (face veil) are stigmatised, criminalised and marked as ‘dangerous’ to British/Western values. Several countries have imposed bans on the wearing of face veils in public places based on the premise that the niqab is a ‘threat’ to notions of gender equality, integration and national security. While the wearing of the niqab has elicited a good deal of media, political and public debates, little attention has been paid to the opinions of Muslim women who wear it. Drawing on individual and focus group interviews with Muslim women who wear the niqab in the United Kingdom (UK), this article places at the centre of the debate the voices of those women who do wear it, and explores their reasons for adopting it. The findings show that the wearing of the niqab emerges as a personal choice, an expression of religious piety, public modesty and belonging to the ‘ummah’. It is also perceived as a form of agency, resistance and non-conformity to Western consumerist culture and lifestyle. It will be concluded that wearing the niqab empowers women in their public presence and offers them a sense of ‘liberation’, which is associated with the notion of anonymity that it provides them

The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence

MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in EμMyc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of EμMyc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established EμMyc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes

The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35

The majority of patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most overexpressed in MYCN-amplified, compared with MYCN-non-amplified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targetsThe authors were supported by National Health & Medical Research Council Australia, National Institutes of Health USA (CA226959-01), Italian Association for Research on Cancer (AIRC), and Cancer Council New South Wales. P.Y.L. is a research fellow of Cancer Institute New South Wales