The tumor suppressor protein PTEN undergoes amyloid-like aggregation in tumor cells

Protein aggregation is an underappreciated mechanism that may contribute to the loss- and oncogenic-gain-of-function of mutant tumor suppressors such as p53 and axin. In the present study, we describe amyloid-like aggregation behaviour of the second most frequently mutated tumor suppressor in human cancer, PTEN. In silico analysis revealed a particularly high aggregation vulnerability for this protein, which was corroborated by in vitro aggregation assays. In cultured tumor cells, we found that under stress conditions, PTEN readily undergoes amyloid-like aggregation as a result of mutation. However, we also show that severe dysregulation of protein homeostasis may lead to aggregation of wild-type PTEN. These observations were supported by a small survey of patient-derived uterine tumor tissues, which found that more than 25% of tumors analyzed displayed wild-type PTEN aggregation. Finally, in an exploratory clinical study we found that PTEN aggregation status was correlated with a decline in clinical outcome. Our findings establish that the tumor suppressor PTEN is highly aggregation-prone and our work suggests that protein aggregation might be an underestimated but prevalent component of cancer cell biology.

Frizzled receptors in tumors, focusing on signaling, roles, modulation mechanisms, and targeted therapies

Wnt molecules play crucial roles in development and adult homeostasis through their receptors Frizzled proteins (Fzds). Fzds mediate canonical β-catenin pathway and various non-canonical β-catenin-independent pathways. Aberrant Fzd signaling is involved in many diseases including cancer. Wnt/β-catenin is a well-established oncogenic pathway involved in almost every aspects of tumor development. However, Fzd-mediated non-canonical Wnt pathways function as both tumor promoters and tumor suppressors depending on cellular context. Fzd-targeted therapies have proven to be effective on cultured tumor cells, tumor cell xenografts, mouse tumor models and patient-derived xenografts (PDX). Moreover, Fzd-targeted therapies synergize with chemotherapy in preclinical models. However, the occurrence of fragility fractures in patients treated with Fzd-targeted agents such as OMP-54F28 and OMP-18R5 limits the development of this combination. Along with new insights on signaling, roles, and modulation mechanisms of Fzds in human tumors, more Fzd-related therapeutic targets will be developed.

Synthesis and Biological Evaluation of New 3,4-diarylmaleimides as Enhancers (modulators) of Doxorubicin Cytotoxic Activity on Cultured Tumor Cells from a Real Case of Breast Cancer

<p>A series of new 3,4-diarylmaleimides were synthesized in an optimized and efficient lineal sequence of three steps, starting from commercial maleimide. The biological evaluation of these compounds as enhancers (activity modulators) in the co-administration with doxorubicin treatment in breast cancer cells directly obtained from a patient, were essayed. The cancerous tissue BT026-512N was provided by the National Institute of Cancerology (INCAN) of México. This tissue was obtained by biopsy from a patient diagnosed with stage IIB ductal breast cancer. The results obtained in the assays, show decreased cell viability on the cultured cells for all of the maleimides synthesized in combinatorial administration with doxorubicin. The highest mortality effect was determined for maleimides <strong>9</strong> and <strong>29</strong> increased in close to three times the effect compared with treatment using only doxorubicin. Based on previous functionalized maleimides core reports and Molinspiration chemoinformatic analysis, these results could possibly point out to the Pg-p glycoprotein as bio-molecular action target of maleimides by kinase phosphorylation-inhibition, although more experimental data is necessary.</p>

The purine receptor P2X7R regulates the release of pro-inflammatory cytokines in human craniopharyngioma

Craniopharyngiomas (CPs) are usually benign, non-metastasizing embryonic malformations originating from the sellar area. They are, however, locally invasive and generate adherent interfaces with the surrounding brain parenchyma. Previous studies have shown the tumor microenvironment is characterized by a local abundance of adenosine triphosphate (ATP), infiltration of leukocytes and elevated levels of pro-inflammatory cytokines that are thought to be responsible, at least in part, for the local invasion. Here, we examine whether ATP, via the P2X7R, participates in the regulation of cytokine expression in CPs. The expression of P2X7R and pro-inflammatory cytokines were measured at the RNA and protein levels both in tumor samples and in primary cultured tumor cells. Furthermore, cytokine modulation was measured after manipulating P2X7R in cultured tumor cells by siRNA-mediated knockdown, as well as pharmacologically by using selective agonists and antagonists. The following results were observed. A number of cytokines, in particular IL-6, IL-8 and MCP-1, were elevated in patient plasma, tumor tissue and cultured tumor cells. P2X7R was expressed in tumor tissue as well as in cultured tumor cells. RNA expression as measured in 48 resected tumors was positively correlated with the RNA levels of IL-6, IL-8 and MCP-1 in tumors. Furthermore, knockdown of P2X7R in primary tumor cultures reduced, and stimulation of P2XR7 by a specific agonist enhanced the expression of these cytokines. This latter stimulation involved a Ca2+-dependent mechanism and could be counteracted by the addition of an antagonist. In conclusion, the results suggest that P2X7R may promote IL-6, IL-8 and MCP-1 production and secretion and contribute to the invasion and adhesion of CPs to the surrounding tissue.