title: Endoplasmic Reticulum Ca(2+) Handling and Apoptotic Resistance in Tumor-Derived Endothelial Colony Forming Cells.
abstract: Truly endothelial progenitor cells (EPCs) can be mobilized from bone marrow to support the vascular network of growing tumors, thereby sustaining the metastatic switch. Endothelial colony forming cells (ECFCs) are the only EPC subtype belonging to the endothelial phenotype and capable of incorporating within neovessels. The intracellular Ca(2+) machinery plays a key role in ECFC activation and is remodeled in renal cellular carcinoma-derived ECFCs (RCC-ECFCs). Particularly, RCC-ECFCs seems to undergo a drop in endoplasmic reticulum (ER) Ca(2+) concentration ([Ca(2+) ]ER ). This feature is remarkable when considering that inositol-1,4,5-trisphosphate (InsP3 )-dependent ER-to-mitochondria Ca(2+) transfer regulates the intrinsic apoptosis pathway. Herein, we sought to assess whether: (1) the [Ca(2+) ]ER and the InsP3 -induced ER-mitochondria Ca(2+) shuttle are reduced in RCC-ECFCs; and (2) the dysregulation of ER Ca(2+) handling leads to apoptosis resistance in tumor-derived cells. RCC-ECFCs displayed a reduction both in [Ca(2+) ]ER and in the InsP3 -dependent mitochondrial Ca(2+) uptake, while they expressed normal levels of Bcl-2 and Bak. The decrease in [Ca(2+) ]ER was associated to a remarkable ER expansion in RCC-ECFCs, which is a hallmark of ER stress, and did not depend on the remodeling of the Ca(2+) -transporting and the ER Ca(2+) -storing systems. As expected, RCC-ECFCs were less sensitive to rapamycin- and thapsigargin-induced apoptosis; however, buffering intracellular Ca(2+) levels with BAPTA dampened apoptosis in both cell types. Finally, store-operated Ca(2+) entry was seemingly uncoupled from the apoptotic machinery in RCC-ECFCs. Thus, the chronic underfilling of the ER Ca(2+) pool could confer a survival advantage to RCC-ECFCs and underpin RCC resistance to pharmacological treatment. J. Cell. Biochem. 117: 2260-2271, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Center for the Study of Myelofibrosis, Biotechnology Research Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Poletto
authors.affiliation: Laboratory of General Physiology, Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, 27100, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Dragoni
authors.affiliation: Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, 28100, Italy.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lim
authors.affiliation: Laboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, 27100, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Biggiogera
authors.affiliation: Center for the Study of Myelofibrosis, Biotechnology Research Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Aronica
authors.affiliation: Department of Public Health, University of Naples "Federico II", Naples, 80131, Italy.
authors.forename: Mariapia
authors.initials: M
authors.lastname: Cinelli
authors.affiliation: Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, Second University of Naples, Largo Madonna delle Grazie 1, Naples, 80138, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Center for the Study of Myelofibrosis, Biotechnology Research Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Medical Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.affiliation: Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, 86100, Italy.
authors.forename: Germano
authors.initials: G
authors.lastname: Guerra
authors.affiliation: Laboratory of General Physiology, Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, 27100, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Moccia
mesh_terms: D000328:Adult; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology*; D066026:Endothelial Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D002118:Calcium
keywords: APOPTOSIS; CALCIUM SIGNALING; CANCER; ENDOTHELIAL PROGENITOR CELLS