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నైరూప్య

IRE-1alpha Signaling as a Key Target for Suppression of Tumor Growth

Oleksandr H. Minchenko, Dariia O. Tsymbal and Dmytro O. Minchenko

Activation of cell proliferation and surviving as well as an increased angiogenesis are important for tumor growth through signaling pathways of the unfolding protein response/endoplasmic reticulum stress, which is a fundamental phenomenon for secure protection of cells by maintaining the functional integrity of the endoplasmic reticulum. The unfolding protein response aims to resolve stress by expanding the protein-folding apparatus, decreasing the load of newly synthesized proteins, and enhancing the degradation and removal of improperly folded proteins from the endoplasmic reticulum by a process termed ERAD (endoplasmic reticulum-associated degradation). Endoplasmic reticulum stress is mediated by three sensor and signaling pathways (PERK, ATF6, and IRE-1α), which are important for tumor cell survival and proliferation, but the IRE-1α signaling is more significant. It is important to note that the aberrant IRE-1α signaling occurs in various cancers and thus can serve as a target for the development of new treatment of these disorders. The inhibition of IRE-1α leads to a decrease of tumor growth through suppression of angiogenesis and cell proliferation and activation of tumor suppressor and some apoptotic genes. Data concerning the molecular mechanisms of the effect an inhibition of IRE-1α signaling enzyme on glioma growth is discussed, including the changes in the expression of genes controlling angiogenesis, cell proliferation, and cell cycle. A better understanding of the biological role of IRE-1α is necessary to develop novel, original IRE-1α modulators and help to define the best therapeutic targets for the design of effective antitumor drug.