Rapamycin

Coevolution of neoplastic epithelial cells and multilineage stroma via polyploid giant cells during immortalization and transformation of mullerian epithelial cells ABSTRACT Stromal cells are generally considered to be derived primarily from the host’s normal mesenchymal stromal cells or bone marrow. However, the origins of stromal cells have been quite controversial. To determine the role of polyploidy in tumor development, we examined the fate of normal mullerian epithelial cells during the immortalization and transformation process by tracing the expression of SV40 large T antigen. Here we show that immortalized or  HRAS -transformed mullerian epithelial cells contain a subpopulation of polyploid giant cells that grow as multicellular spheroids expressing hematopoietic markers in response to treatment with CoCl 2 . The immortalized or transformed epithelial cells can transdifferentiate into stromal cells when transplanted into nude mice. Immunofluorescent staining revealed expressio

All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to Ponatinib ABSTRACT The advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechan

Recent progress in genetics of aging, senescence and longevity: focusing on cancer-related genes ABSTRACT It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the “hyperfunction theory”, which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin). These pathways consist of different enzymes, mostly kinases, but also phosphatases, deacetylases, GTPases, and some other molecules that cause overactivation of normal cellular functions. Overactivation of these sensory signal transduction pathways can cause cellular senescence, age-related diseases, including cancer, and shorten life span. Here we review some of the numerous very recent publications on the role of signal transduction molecules in aging and age-related diseases. As was emphasized

Advances in Targeting Signal Transduction Pathways. ABSTRACT Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies. oncotarget acceptance rate Misha Blagosklonny Mikhail (Misha) V. Blagosklonny graduated

Modulating Antiangiogenic Resistance by Inhibiting the Signal Transducer and Activator of Transcription 3 Pathway in Glioblastoma ABSTRACT Determining the mechanism of treatment failure of VEGF signaling inhibitors for malignant glioma patients would provide insight into approaches to overcome therapeutic resistance. In this study, we demonstrate that human glioblastoma tumors failing bevacizumab have an increase in the mean percentage of p-STAT3-expressing cells compared to samples taken from patients failing non-antiangiogenic therapy containing regimens. Likewise, in murine xenograft models of glioblastoma, the mean percentage of p-STAT3-expressing cells in the gliomas resistant to antiangiogenic therapy was markedly elevated relative to controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced the infiltration of VEGF inhibitor-induced p-STAT3 macrophages. Thus, the combination of AZD1480 with cediranib markedly reduced tumor volume

DNA damage-induced activation of ATM promotes β-TRCP-mediated Mdm2 ubiquitination and destruction ABSTRACT The Mdm2 oncoprotein promotes p53 ubiquitination and destruction. Yet, exact molecular mechanisms of Mdm2 destruction itself, under DNA damaging conditions, remain unclear. Recently, we identified SCF β-TRCP  as a novel E3 ligase that targets Mdm2 for ubiquitination and destruction in a Casein Kinase Iδ (CKIδ)-dependent manner. However, it remains elusive how the β-TRCP/CKIδ/Mdm2 signaling axis is regulated by DNA damage signals to govern p53 activity. Consistent with previous studies, we found that inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase, in turn, impaired DNA damage-induced Mdm2 destruction. Although phosphorylation of Mdm2 at Ser395 (an ATM phosphorylation site) facilitated Mdm2 interaction with β-TRCP, Ser395A-Mdm2 was degraded non-distinguishably from WT-Mdm2 by SCF β-TRCP  upon DNA damaging treatments. This indicates that in addition to phosphorylating

Phenotypic Screening Reveals Topoisomerase I as a Breast Cancer Stem Cell Therapeutic Target ABSTRACT Cancer stem cells (CSCs) are a subpopulation generally thought to be responsible for cancer initiation and progression. Because CSCs are often rare in the total tumor cell population and differentiate rapidly when grown in culture, it has been challenging to uncover compounds that selectively target CSCs. We previously described CSC-emulating cells derived from breast cancer cell lines that maintained a stable undifferentiated state. We optimized a phenotypic assay with these cells and screened 1,280-bioactive compounds, identifying five that preferentially inhibited CSC-like cell proliferation. Using a compound-guided target identification approach, we found high topoisomerase I (Topo I) expression levels in breast CSC-like cells and primary breast CSCs. Structurally unrelated small molecules targeting Topo I preferentially inhibited CSC-like cells. These results illustrate the substa

Perifosine Inhibits Multiple Signaling Pathways in Glial Progenitors and Cooperates With Temozolomide to Arrest Cell Proliferation in Gliomas  Abstract Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in ∼70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model  in vivo . Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G 1  and G 2 , and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we investigated the

Novel Fusion Protein Approach for Efficient High-Throughput Screening of Small Molecule–Mediating Protein-Protein Interactions in Cells and Living Animals Abstract Networks of protein interactions execute many different intracellular pathways. Small molecules either synthesized within the cell or obtained from the external environment mediate many of these protein-protein interactions. The study of these small molecule–mediated protein-protein interactions is important in understanding abnormal signal transduction pathways in a variety of disorders, as well as in optimizing the process of drug development and validation. In this study, we evaluated the rapamycin-mediated interaction of the human proteins FK506-binding protein (FKBP12) rapamycin-binding domain (FRB) and FKBP12 by constructing a fusion of these proteins with a split- Renilla  luciferase or a split enhanced green fluorescent protein (split-EGFP) such that complementation of the reporter fragments occurs in the presence of

Signaling through IFN Regulatory Factor-5 Sensitizes p53-Deficient Tumors to DNA Damage–Induced Apoptosis and Cell Death Abstract Human IFN regulatory factor-5 (IRF-5) is a candidate tumor suppressor gene that mediates cell arrest, apoptosis, and immune activation. Here we show that ectopic IRF-5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage–induced apoptosis. The combination IFN-β and irinotecan (CPT-11) cooperatively inhibits cell growth and IRF-5 synergizes with it to further promote apoptosis. The synergism is due to IRF-5 signaling since a striking defect in apoptosis and cell death was observed in IRF-5-deficient cells, which correlated well with a reduction in DNA damage–induced cellular events. Components of this IRF-5 signaling pathway are investigated including a mechanism for DNA damage–induced IRF-5 activation. Thus, IRF-5–regulated pathways may serve as a target for cancer therapeutics.  https://cancerres.aacrjournals.org/content/65/16/7403

Why human lifespan is rapidly increasing: solving "longevity riddle" with "revealed-slow-aging" hypothesis.  Mikhail V. Blagosklonny Abstract Healthy life span is rapidly increasing and human aging seems to be postponed. As recently exclaimed in Nature, these findings are so perplexing that they can be dubbed the 'longevity riddle'. To explain current increase in longevity, I discuss that certain genetic variants such as hyper-active mTOR (mTarget of Rapamycin) may increase survival early in life at the expense of accelerated aging. In other words, robustness and fast aging may be associated and slow-aging individuals died prematurely in the past. Therefore, until recently, mostly fast-aging individuals managed to survive into old age. The progress of civilization (especially 60 years ago) allowed slow-aging individuals to survive until old age, emerging as healthy centenarians now. I discuss why slow aging is manifested as postponed (healthy) aging, why the