The endoplasmic reticulum and its signaling pathways - a novel target for multiple myeloma treatment.

BACKGROUND: The endoplasmic reticulum (ER), an organelle composed of a system of cisternae and tubules, is essential for many cellular processes, including protein synthesis and transport. When misfolded proteins accumulate in the ER lumen, ER stress is induced, and the subsequent response to the disruption of homeostasis is the activation of the unfolded protein response (UPR). The purpose of this process is to restore homeostasis by increasing the capacity of the ER and its ability to fold proteins. Activation of the homeostatic UPR occurs via one of three transmembrane proteins, inositol-requiring enzyme 1a (IRE1a), protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Failure of the attempt to restore homeostasis, on the other hand, leads to the development of terminal UPR and apoptosis via hyperactivation of the same proteins. Activation of UPR has been described in many malignancies, including multiple myeloma (MM), which is characterized by malignant transformation of plasma cells and increased monoclonal immunoglobulin synthesis, where the role of the ER is of particular importance. Despite advances in the treatment of MM, the disease remains difficult to treat and targeting signaling pathways associated with the UPR could, for example, enhance the effect of proteasome inhibitors. PURPOSE: This review intends to present the molecular response to ER stress under physiological circumstances and in the context of cancer, particularly with regard to potential therapeutic targets in MM.

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

Deregulation of expression and function of cytokines belonging to the transforming growth factor-ß (TGF-ß) family is often associated with various pathologies. For example, this cytokine family has been considered a promising target for cancer therapy. However, the detailed functions of several cytokines from the TGF-ß family that could have a role in cancer progression and therapy remain unclear. One of these molecules is growth/differentiation factor-15 (GDF-15), a divergent member of the TGF-ß family. This stress-induced cytokine has been proposed to possess immunomodulatory functions and its high expression is often associated with cancer progression, including prostate cancer (PCa). However, studies clearly demonstrating the mechanisms for signal transduction and functions in cell interaction, cancer progression and therapy are still lacking. New GDF-15 roles have recently been identified for modulating osteoclast differentiation and for therapy for PCa bone metastases. Moreover, GDF-15 is as an abundant cytokine in seminal plasma with immunosuppressive properties. We discuss studies that focus on the regulation of GDF-15 expression and its role in tissue homeostasis, repair and the immune response with an emphasis on the role in PCa development.

[Regulation of osteoclast activity: a new approach in the therapy of bone diseases]. / Regulace aktivity osteoklastu: prostor pro terapii nekterých onemocnení kostí.

Bone remodelling is process of constant resorption and formation of a bone. Osteoclasts are the cells responsible for bone resorption. Deregulation of osteoclast differentiation, activity or function can cause severe diseases, such as osteoporosis, osteopetrosis or rheumatoid arthritis. Advances in molecular biology of osteoclasts and osteoimmunology open new approaches for the specific and efficient therapy.