Long Noncoding RNA in Cancer: Wiring Signaling Circuitry

Eukaryotic elongation factor 2 kinase (eEF2K) is a member of the small group of atypical 'α-kinases'. It phosphorylates and inhibits eukaryotic elongation factor 2, to slow down the elongation stage of protein synthesis, which normally consumes a great deal of energy and amino acids. The activity of eEF2K is normally dependent on calcium ions and calmodulin. eEF2K is also regulated by a plethora of other inputs, including inhibition by signalling downstream of anabolic signalling pathways such as the mammalian target of rapamycin complex 1. Recent data show that eEF2K helps to protect cancer cells against nutrient starvation and is also cytoprotective in other settings, including hypoxia. Growing evidence points to roles for eEF2K in neurological processes such as learning and memory and perhaps in depression.

Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles.

Resistance to therapy is one of the prime causes for treatment failure in cancer and recurrent disease. In recent years, autophagy has emerged as an important cell survival mechanism in response to different stress conditions that are associated with cancer treatment and aging. Autophagy is an evolutionary conserved catabolic process through which damaged cellular contents are degraded after uptake into autophagosomes that subsequently fuse with lysosomes for cargo degradation, thereby alleviating stress. In addition, autophagy serves to maintain cellular homeostasis by enriching nutrient pools. Although autophagy can act as a double-edged sword at the interface of cell survival and cell death, increasing evidence suggest that in the context of cancer therapy-induced stress responses, it predominantly functions as a cell survival mechanism. Here, we provide an up-to-date overview on our current knowledge of the role of pro-survival autophagy in cancer therapy at the preclinical and clinical stages and delineate the molecular mechanisms of autophagy regulation in response to therapy-related stress conditions. A better understanding of the interplay of cancer therapy and autophagy may allow to unveil new targets and avenues for an improved treatment of therapy-resistant tumors in the foreseeable future.

Pro-survival autophagy and cancer cell resistance to therapy

Stress-mediated translational control in cancer cells.

Non-coding RNAs (ncRNAs) constitute a heterogeneous group of RNA molecules in terms of biogenesis, biological function as well as length and structure. These biological molecules have gained attention recently as a potentially crucial layer of tumor cell progression or regulation. ncRNAs are expressed in a broad spectrum of tumors, and they play an important role not only in maintaining but also in promoting cancer development and progression. Recent discoveries have revealed that ncRNAs may act as key signal transduction mediators in tumor signaling pathways by interacting with RNA or proteins. These results reinforce the hypothesis, that ncRNAs constitute therapeutic targets, and point out their clinical potential as stratification markers. The major purpose of this review is to mention the emergence of the importance of ncRNAs, as molecules which are correlated with cancer, and to discuss their clinical implicit as prognostic diagnostic indicators, biomarkers, and therapeutic targets.

Non-coding RNAs: the riddle of the transcriptome and their perspectives in cancer.

Eukaryotic elongation factor 2 kinase (eEF-2K), through its phosphorylation of elongation factor 2 (eEF2), provides a mechanism by which cells can control the rate of the elongation phase of protein synthesis The activity of eEF-2K is increased in rapidly proliferating malignant cells, is inhibited during mitosis, and may contribute to the promotion of autophagy in response to anti-cancer therapies The purpose of this study was to examine the therapeutic potential of targeting eEF-2K in breast cancer tumors Through the systemic administration of liposomal eEF-2K siRNA (twice a week, iv 150 µg/kg), the expression of eEF-2K was down-regulated in vivo in an orthotopic xenograft mouse model of a highly aggressive triple negative MDA-MB-231 tumor This targeting resulted in a substantial decrease in eEF2 phosphorylation in the tumors, and led to the inhibition of tumor growth, the induction of apoptosis and the sensitization of tumors to the chemotherapy agent doxorubicin eEF-2K down-modulation in vitro resulted in a decrease in the expression of c-Myc and cyclin D1 with a concomitant increase in the expression of p27Kip1 A decrease in the basal activity of c-Src (phospho-Tyr-416), focal adhesion kinase (phospho-Tyr-397), and Akt (phospho-Ser-473) was also detected following eEF-2K down-regulation in MDA-MB-231 cells, as determined by Western blotting Where tested, similar results were seen in ER-positive MCF-7 cells These effects were also accompanied by a decrease in the observed invasive phenotype of the MDA-MB-231 cells These data support the notion that the disruption of eEF-2K expression in breast cancer cells results in the down-regulation of signaling pathways affecting growth, survival and resistance and has potential as a therapeutic approach for the treatment of breast cancer

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Targeted Silencing of Elongation Factor 2 Kinase Suppresses Growth and Sensitizes Tumors to Doxorubicin in an Orthotopic Model of Breast Cancer

Natural killer (NK) cells have potential utility in pediatric cancer immunotherapy for their ability to lyse diverse tumor targets, lack of dependence on mutation-associated tumor antigens, and for their relative safety demonstrated so far in clinical trials. Here, we evaluate the cytotoxic potential of expanded NK cells against a well-characterized panel of pediatric cancer cell lines representing Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, lymphoma, leukemia, and brain tumors. We correlate their sensitivity NK cell lysis with tumor phenotypic, transcriptomic, and genetic determinants, and correlate known immunogenetic determinants with donor NK cell potency. Although ligand expression on cell lines stratified according to hematologic versus nonhematologic cancer types, the sensitivity to NK cell lysis varied widely and did not correlate with cancer type, expression of individual activating or inhibitory ligands, gene-expression clusters of NK cell ligands, disease status (newly diagnosed or relapsed), or MYCN amplification. Rather, sensitivity to NK cell-mediated lysis was associated with a novel 96-gene cluster of predominantly carcinoma-, apoptosis-, and cell death-related pathways, and with functional p53 status. NK cell potency was strongly associated with activating KIR gene content, but not with KIR/KIR-ligand mismatch. This study suggests that adoptive immunotherapy with expanded NK cells has the potential for a wide range of pediatric cancers, identifies potential biomarkers of efficacy and response, and establishes a foundation for using this cell line panel for the preclinical evaluation of immunotherapies.

Expression of carcinoma, apoptosis, and cell-death-related genes are determinants for sensitivity of pediatric cancer cell lines to lysis by natural killer cells.

Zehra E. Cobanoglu

Papers

Targeted Silencing of Elongation Factor 2 Kinase Suppresses Growth and Sensitizes Tumors to Doxorubicin in an Orthotopic Model of Breast Cancer

Expression of carcinoma, apoptosis, and cell-death-related genes are determinants for sensitivity of pediatric cancer cell lines to lysis by natural killer cells.

Optimal Cryopreservation Conditions to Preserve Viability, Proliferation, and Lytic Function of