Targeting Stim and Orai Proteins as an Alternative Approach in Anticancer Therapy

Abstract

An increase in intracellular Ca2+ concentration plays a key role in the establishment of many cancer hallmarks, including aberrant proliferation, migration, invasion, resistance to apoptosis and angiogenesis. The dysregulation of Ca2+ entry is one of the most subtle mechanisms by which cancer cells overwhelm their normal counterparts and gain the adaptive advantages that result in tumour growth, vascularisation and dissemination throughout the organism. Both constitutive and agonist-induced Ca2+ influx may be mediated by store-dependent as well as store-independent Ca2+ entry routes. A growing body of evidences have shown that different isoforms of Stromal Interaction Molecules (Stim1) and Orai proteins, i.e. Stim1, Stim2, Orai1 and Orai3, underlie both pathways in cancer cells. The alteration in either the expression or the activity of Stim and Orai proteins has been linked to the onset and maintenance of tumour phenotype in many solid malignancies, including prostate, breast, kidney, esophageal, skin, brain, colorectal, lung and liver cancers. Herein, we survey the existing data in support of Stim and Orai involvement in tumourigenesis and provide the rationale to target them in cancer patients. Besides, we summarize the most recent advances in the identification of novel pharmacological tools that could be successfully used in clinical therapy.

Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis

“…In mammals there are three Orai genes that encode for Orai1, 2 and 3 proteins which function as pore forming subunits of CRAC channels in different cellular contexts [10,12,20,42,50]. The name Orai was given on the basis of Greek mythology (Orai are the keepers of heaven’s gate) after they were established as the long sought mediator of CRAC currents in immune cells [51].…”

“…Although originally identified as a mechanism for ensuring the refilling of intracellular stores following Ca 2+ release [15,16], SOCE is now directly linked to the activation of specific cellular functions, differently regulated depending on the stimulus and the cell type [10], including immune system activation [17], fluid secretion in salivary gland acinar cells [18], neurogenesis and neuronal excitability [12,19], cancer cell migration and metastasis [20], endothelial cell proliferation [21], skeletal muscle contractility [22], smooth muscle migration and proliferation [23,24], cardiac hypertrophy [25], cell cycle and cell proliferation [26], and gene expression [27]. Further, increasing evidences have recently identified the contribution of SOCE in thrombopoiesis, the process that ensures the differentiation of megakaryocytes, the platelet precursors, and final platelet production [28].…”

TRPC3‐mediated Ca2+ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

“…It has long been known that an increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) plays a key role in the complex and multistepped process of angiogenesis (Moccia, Berra‐Romani, & Tanzi, ; Moccia, Tanzi, & Munaron, ). This notion dates back to the earlier experiments conducted with carboxyamidotriazole, a non‐selective inhibitor of a plethora of Ca 2+ ‐permeable channels (Dragoni, Turin, et al, ; Moccia, Dragoni, et al, ; Moccia et al, ), that was shown to inhibit angiogenesis both in vitro and in vivo (Kohn, Alessandro, Spoonster, Wersto, & Liotta, ; Moccia et al, ; Patton, Kassis, Doong, & Kohn, ). An elevation in [Ca 2+ ] i represents a critical hub for the intricate network of signaling pathways evoked by extracellular growth factors (Moccia, ; Moccia, Berra‐Romani, & Tanzi, ; Moccia & Poletto, ; Moccia, Tanzi, & Munaron, ).…”

Inhibition of Orai1‐mediated Ca2+ entry enhances chemosensitivity of HepG2 hepatocarcinoma cells to 5‐fluorouracil

“…Upon ER store depletion, STIM1 aggregates and translocates to plasma membrane and then interacts directly with Orai1 and/or TRPC1 to form open SOCs that cause SOCE . Interestingly, the three constituents of SOCE, Stim1, Orai1 and TRPC1, have been detected in liver cells and associated with the initiation and progression of liver cancer . Previous work in HCC‐LM3 hepatoma cells showed that blockade of STIM‐mediated SOCE decreased the focal adhesion turnover and thus inhibited cell migration .…”