The lysosomal degradation pathway known as autophagy has an essential homeostatic role in controlling the quality of the cytoplasm. However, this pathway has also been implicated in the pathology of an array of human disorders. Here, Rubinsztein and colleagues provide an overview of the mechanisms and regulation of autophagy, discuss the role of this pathway in disease and highlight potential strategies for therapeutic modulation.

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Autophagy modulation as a potential therapeutic target for diverse diseases

Anti-cancer drugs

Mast cells are important effector cells of the immune system and recent studies show that they have immunomodulatory roles in diverse processes in both health and disease. Mast cells are distinguished by their high content of electron-dense secretory granules, which are filled with large amounts of preformed and pre-activated immunomodulatory compounds. When appropriately activated, mast cells undergo degranulation, a process by which these preformed granule compounds are rapidly released into the surroundings. In many cases, the effects that mast cells have on an immune response are closely associated with the biological actions of the granule compounds that they release, as exemplified by the recent studies showing that mast cell granule proteases account for many of the protective and detrimental effects of mast cells in various inflammatory settings. In this Review, we discuss the current knowledge of mast cell secretory granules.

Mast cell secretory granules: armed for battle

EGFR-Mediated Beclin 1 Phosphorylation in Autophagy Suppression, Tumor Progression, and Tumor Chemoresistance

Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer.

Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs: A beneficial strategy to combat non-small cell lung cancer

Mast cells are directly activated by contact with cancer cells by a mechanism involving autocrine formation of adenosine and autocrine/paracrine signaling of the adenosine A3 receptor.

Neuronal and non-neuronal tissues show distinctly different intracellular localization of synaptotagmin (Syt) homologues. Therefore, cell type-specific mechanisms are likely to direct Syt homologues to their final cellular destinations. Syt IX localizes to dense core vesicles in PC12 cells. However, in the rat basophilic leukemia (RBL-2H3) mast cell line, as well as in CHO cells, Syt IX is localized at the endocytic recycling compartment (ERC). We show that targeting of Syt IX to the ERC involves constitutive trafficking to the plasma membrane followed by internalization and transport to the ERC. We further show that internalization from the plasma membrane and delivery to the ERC are dependent on phosphorylation by Ca(2+)-dependent protein kinase Calpha or beta. As such, correct targeting of Syt IX is facilitated by the phorbol ester TPA but prevented by the cPKC inhibitor Go 6976.

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Classical protein kinase C(s) regulates targeting of synaptotagmin IX to the endocytic recycling compartment.

Mast Cells Are Directly Activated by Cancer Cell-Derived Extracellular Vesicles by a CD73- and Adenosine-Dependent Mechanism.

Accumulating evidence has highlighted the accumulation of mast cells (MCs) in tumors. However, their impact on tumor development remained controversial. Indeed, cumulative data indicate an enigmatic role for MCs in cancer, whereby depending on the circumstances, which still need to be resolved, MCs function to promote or restrict tumor growth. By responding to multiple stimuli MCs release multiple inflammatory mediators, that contribute to the resolution of infection and resistance to envenomation, but also have the potency to promote or inhibit malignancy. Thus, MCs seem to possess the power to define tumor projections. Given this remarkable plasticity of MC responsiveness, there is an urgent need of understanding how MCs are activated in the tumor microenvironment (TME). We have recently reported on the direct activation of MCs upon contact with cancer cells by a mechanism involving an autocrine formation of adenosine and signaling by the A3 adenosine receptor. Here we summarized the evidence on the role of adenosine signaling in cancer, in MC mediated inflammation and in the MC-cancer crosstalk.

/pdf/role-of-mast-cell-derived-adenosine-in-cancer-2cybmxrace.pdf

Yaara Gorzalczany

Papers

Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs: A beneficial strategy to combat non-small cell lung cancer

Mast cells are directly activated by contact with cancer cells by a mechanism involving autocrine formation of adenosine and autocrine/paracrine signaling of the adenosine A3 receptor.

Classical protein kinase C(s) regulates targeting of synaptotagmin IX to the endocytic recycling compartment.

Mast Cells Are Directly Activated by Cancer Cell-Derived Extracellular Vesicles by a CD73- and Adenosine-Dependent Mechanism.

Role of Mast Cell-Derived Adenosine in Cancer.