title: The endoplasmic reticulum mitochondrial calcium cross talk is downregulated in malignant pleural mesothelioma cells and plays a critical role in apoptosis inhibition.
abstract: The failure of apoptosis may contribute to the formation of cancer and to its resistance to therapy. Malignant pleural mesothelioma (MPM) is an aggressive tumor that responds poorly to standard chemo- and radio-therapies. Several studies have demonstrated that a plethora of oncogenes and tumor suppressors contribute to MPM onset/progression. Importantly, most of these genes are involved in the regulation of calcium (Ca2+)-handling. Cellular Ca2+ signaling is an important regulator of many physiological processes, and it has been widely reported to participate in the regulation of apoptotic cell death in cancer cells and tissues. However, in MPM the role of cellular Ca2+ has been poorly investigated. Therefore, we examined whether Ca2+ is involved in MPM. We found that mesothelioma cell lines and short-term cultures obtained from MPM-affected patients exhibited a critical dysregulation in Ca2+ signaling. We determined that this characteristic was associated with resistance to apoptotic stimuli and that correction of intracellular Ca2+ signaling resulted in the rescue of efficient apoptotic responses. In addition, we discovered that mitochondrial Ca2+-uptake plays a pivotal role as an inducer of apoptosis in MPM. Altogether, these findings suggest the identification of new MPM markers, which in turn could be potential targets for new therapeutic approaches.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Patergnani
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Maniero
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Missiroli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of General and Thoracic Surgery, University of Ferrara, Ferrara, Italy.
authors.forename: Pio
authors.initials: P
authors.lastname: Maniscalco
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bononi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Martini
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavallesco
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Tognon
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
mesh_terms: D000328:Adult; D000331:Aequorin / Q000737:chemistry; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001706:Biopsy; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism*; D000086002:Mesothelioma, Malignant; D008928:Mitochondria / Q000378:metabolism*; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D000331:Aequorin; D002118:Calcium
keywords: apoptosis; calcium; mesothelioma; mitochondria; therapy