دانلود رایگان ترجمه مقاله کانال های کلسیم غشای پلاسما در سرطان – الزویر 2015

کانال های کلسیم غشای پلاسما در سرطان: تغییرات و اثرات تکثیر و مهاجرت سلول

Plasma membrane calcium channels in cancer: Alterations and consequences for cell proliferation and migration

Abstract

The study of calcium channels in molecular mechanisms of cancer transformation is still a novel area of research. Several studies, mostly conducted on cancer cell lines, however support the idea that a diversity of plasma membrane channels participates in the remodeling of Ca2 + homeostasis, which regulates various cancer hallmarks such as uncontrolled multiplication and increase in migration and invasion abilities. However few is still understood concerning the intracellular signaling cascades mobilized by calcium influx participating to cancer cell behavior. This review intends to gather some of these pathways dependent on plasma membrane calcium channels and described in prostate, breast and lung cancer cell lines. In these cancer cell types, the calcium channels involved in calcium signaling pathways promoting cancer behaviors are mostly non-voltage activated calcium channels and belong to the TRP superfamily (TRPC, TPRPV and TRPM families) and the Orai family. TRP and Orai channels are part of many signaling cascades involving the activation of transmembrane receptors by extracellular ligand from the tumor environment. TRPV can sense changes in the physical and chemical environment of cancer cells and TRPM7 are stretch activated and sensitive to cholesterol. Changes in activation and or expression of plasma-membrane calcium channels affect calcium-dependent signaling processes relevant to tumorigenesis. The studies cited in this review suggest that an increase in plasma membrane calcium channel expression and/or activity sustain an elevated calcium entry (constitutive or under the control of extracellular signals) promoting higher cell proliferation and migration in most cases. A variety of non-voltage-operated calcium channels display change expression and/or activity in a same cancer type and cooperate to the same process relevant to cancer cell behavior, or can be involved in a different sequence of events during the tumorigenesis. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

1. Introduction

Tumorigenesis occurs as a result of mutations driving the transformation of cells and the conferring of cancer-specific hallmarks [1], such as self-sufficiency in growth signals and evasion of apoptosis. Many known mutations lead to the formation of oncogenes, which code for protein kinases [2]. Changes in protein kinase activity that integrate with numerous signaling pathways have major consequences for a variety of processes that drive the cell’s fate. Similarly, changes in cytosolic free Ca2+ concentration ([Ca2+]i) represent a ubiquitous signaling mechanism, which integrates with other signal-transduction cascades and controls a variety of cellular processes [3]. As for protein kinase, alterations of calcium signaling and homeostasis induce wide ranging consequences, and it is not surprising that some Ca2+- mediated signaling pathways are implicated in tumorigenesis and tumor progression (refs. [4,5]). The free calcium ion concentration is tightly and precisely controlled in cellular compartments, in order to generate intracellular calcium signals with various amplitudes, as well as different temporal and spatial properties. This precise control is essential for differential modulation, in an individual cell, of various signaling pathways and intracellular Ca2+-regulated proteins involved in specific cellular processes. These include regulation of the cell cycle, proliferation, apoptosis, gene transcription, and cell migration [3]. Since all these functions are relevant to tumorigenesis, the remodeling of intracellular Ca2+ homeostasis and of Ca2+ signals is thought to be a crucial event in leading to, or maintaining, malignant phenotypes. Indeed, tumor transformation is associated with a major rearrangement of Ca2+-transporting molecules (changes in expression and/or function), which participates with other signaling pathways. This may result in enhanced survival (evasion of apoptosis), excessive proliferation, malignant angiogenesis, cell migration and metastasis (refs. [6,7]). Various modifications of Ca2+- transporting molecules and of proteins regulating calcium homeostasis (the Ca2+-toolkit) have been observed and suggested. Among these are mutations; changes in expression level or in subcellular localization; and regulation by other signaling pathways. These changes can lead to modifications of Ca2+ concentration in different cellular compartments and microdomains, as well as changes in intracellular Ca2+ signal patterns. This can contribute to a new cell fate by changing the regulation of various calcium-dependent effectors involved in key intracellular signaling pathways (ref. [7]).