The many-faced KSR1: a tumor suppressor in breast cancer

Emerging evidence supports the dual function of kinase suppressor of Ras 1 (KSR1) as an active kinase and a scaffold, although it has been extensively referred as a pseudokinase, due to the absence of key residues in its catalytic domain [1, 2]. As a scaffolding protein, KSR1 orchestrates the assembly of the protein kinases RAF, mitogen activated protein kinase (MAPK) kinase (MEK), and extracellular signal-regulated kinase (ERK) in the canonical Ras-RAF-MAPKs pathway, in a Ras-dependent manner or upon growth factor treatment [1, 3]. Conversely, structural and biochemical studies reveal that KSR1 is capable of phosphorylating MEK and more importantly, the catalytic activity of KSR is markedly increased when BRAF or inhibitor-bound CRAF is introduced in the complexes [1, 4, 5]. Such findings add complexity to th

Castrate-resistant prostate cancer: the future of antiandrogens

Prostate cancer is the most common non-cutaneous cancer in North American and European men and the second leading cause of male cancer-related death [1]. The lifetime probability of developing prostate cancer in the UK is 14% [1] and in 2010 there were there were 40,975 new cases, accounting for 10,721 deaths [2]. Prostate cancer is associated with many risk factors, including age, family history, ethnicity, diet, and weight and although it is estimated that not more than 5% of all prostate cancer cases are hereditary, family history is appropriately considered a relevant risk factor. Many genetic changes have been associated with prostate cancer, including mutations in P53, P21, and P73 and tumour suppressor genes [3]

The role of LMTK3 in chromatin remodeling and transcriptional regulation

Nuclear receptor tyrosine kinases such as EGFR have been shown to be associated with increased tumor grade and poorer patient survival. One explanation for this is that following nuclear transport, these RTKs are directly involved in the transcriptional regulation through chromatin binding. LMTK3 is a novel oncogenic RTK implicated in breast cancer, whose cytoplasmic and nuclear abundance are highly associated with poorer survival in breast cancer patient. So far the function of the cytoplasmic LMTK3 in breast cancer growth, invasion and endocrine resistance has been addressed, however little is known about the role of nuclear LMTK3. In our recent study, we discovered that LMTK3 binds chromatin via its interacting partners PP1? and KAP1. Moreover, LMTK3 induces the tethering of chromatin to the nuclear periphery. These events result in chromatin condensation and subsequent transcriptional repression of various tumor suppressor-like genes, leading to breast cancer progression. Overall, this research work provides an insight of the nuclear kinase function and suggests that targeting LMTK3 may have further clinical potentials in treating breast cancer

Lemur tyrosine kinase-3 (LMTK3) in cancer and evolution

No description supplie

HIV, hepatitis B and hepatitis C coinfection in Kenya

There are few data regarding hepatitis and HIV coinfection in Africa. In 378 HIV seropositive individuals in Nairobi, 23 (6%) were hepatitis B virus (HBV) and HIV coinfected, four (1%) were hepatitis C virus (HCV) and HIV coinfected and one patient was infected with all three viruses. Coinfected individuals were more likely to be men and older; a lack of HBV vaccination was a risk factor for HIV/HBV coinfection (PU0.001) and tenofovir containing regimens appeared most effective at reducing HBV viral load

Breast Cancer in the Setting of HIV

Oncogenesis in immunocompromised patients occurs due to a number of factors including reduced immune surveillance or other viral pathogens. Breast cancer, unlike other non-AIDS-defining cancers, does not appear associated and has rarely been reported. We describe a case with evidence of immune reactivity around the tumor, but not in the tumor itself

ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation

Acquired or de novo resistance to trastuzumab remains a barrier to patient survival and mechanisms underlying this still remain unclear. Using stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics to compare proteome profiles between trastuzumab sensitive/resistant cells, we identified autophagy related protein 9A (ATG9A) as a down-regulated protein in trastuzumab resistant cells (BT474-TR). Interestingly, ATG9A ectopic expression markedly decreased the proliferative ability of BT474-TR cells but not that of the parental line (BT474). This was accompanied by a reduction of Her2 protein levels and AKT phosphorylation (S473), as well as a decrease in Her2 stability, which was also observed in JIMT1 and MDA-453, naturally trastuzumab-resistant cells. In addition, ATG9A indirectly promoted c-Cbl recruitment to Her2 on T1112, a known c-Cbl docking site, leading to increased K63 Her2 polyubiquitination. Whereas silencing c-Cbl abrogated ATG9A repressive effects on Her2 and downstream PI3K/AKT signaling, its depletion restored BT474-TR proliferative rate. Taken together, our findings show for this first time that ATG9A loss in trastuzumab resistant cells allowed Her2 to escape from lysosomal targeted degradation through K63 poly-ubiquitination via c-Cbl. This study identifies ATG9A as a potentially druggable target to overcome resistance to anti-Her2 blockade

[Letter to editor] Shedding of bevacizumab in tumour cells derived extracellular vesicles as a new therapeutic escape mechanism in glioblastoma

Glioblastoma (GBM) is the most aggressive type of primary brain tumours. Anti-angiogenic therapies (AAT), such as bevacizumab, have been developed to target the tumour blood supply. However, GBM presents mechanisms of escape from AAT activity, including a speculated direct effect of AAT on GBM cells. Furthermore, bevacizumab can alter the intercellular communication of GBM cells with their direct microenvironment. Extracellular vesicles (EVs) have been recently described as main acts in the GBM microenvironment, allowing tumour and stromal cells to exchange genetic and proteomic material. Herein, we examined and described the alterations in the EVs produced by GBM cells following bevacizumab treatment. Interestingly, bevacizumab that is able to neutralise GBM cells-derived VEGF-A, was found to be directly captured by GBM cells and eventually sorted at the surface of the respective EVs. We also identified early endosomes as potential pathways involved in the bevacizumab internalisation by GBM cells. Via MS analysis, we observed that treatment with bevacizumab induces changes in the EVs proteomic content, which are associated with tumour progression and therapeutic resistance. Accordingly, inhibition of EVs production by GBM cells improved the anti-tumour effect of bevacizumab. Together, this data suggests of a potential new mechanism of GBM escape from bevacizumab activity

HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease.

Kaposi sarcoma-associated herpesvirus infection is associated with the development of 3 proliferative diseases: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. These conditions are also intimately associated with human immunodeficiency virus infection, and important synergistic interactions between these 2 viruses have been described. Despite differences in viral gene expression patterns in each condition, Kaposi sarcoma-associated herpesvirus encodes similar oncogenic proteins that promote the activation of sequential and parallel signaling pathways. Therapeutic strategies have been implemented to target these unique signaling pathways, and this sort of molecular targeting is the focus of many current research efforts. The scope of this review is to present contemporary knowledge about the epidemiology, virology, and immunology of Kaposi sarcoma-associated herpesvirus and to highlight several key oncogene products that may be targets for chemotherapy