Targeting Stim and Orai Proteins as an Alternative Approach in Anticancer Therapy.
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.
Laboratory of General Physiology, Department of Biology and Biotechnology &#34;Lazzaro Spallanzani&#34;, University of Pavia, Via Forlanini 6, 27100, Pavia, Italy. francesco.moccia@unipv.it.
Francesco
F
Moccia
Estella
E
Zuccolo
Valentina
V
Poletto
Ilaria
I
Turin
Germano
G
Guerra
Paolo
P
Pedrazzoli
Vittorio
V
Rosti
Camillo
C
Porta
Daniela
D
Montagna
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D020013:Calcium Signaling / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071740:ORAI1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1