Cell Volume in the Regulation of Cell Proliferation and Apoptotic Cell Death

Abstract

Cell proliferation must – at some time point – lead to increase of cell volume and one of the hallmarks of apoptosis is cell shrinkage. At constant extracellular osmolarity those alterations of cell volume must reflect respective changes of cellular osmolarity which are hardly possible without the participation of cell volume regulatory mechanisms. Indeed, as shown for ras oncogene expressing 3T3 fibroblasts, cell proliferation is paralleled by activation of Na⁺/H⁺ exchange and Na⁺,K⁺,2Cl^- cotransport, the major transport systems accomplishing regulatory cell volume increase. Conversely, as evident from CD95-induced apoptotic cell death, apoptosis is paralleled by inhibition of Na⁺/H⁺ exchanger and by activation of Cl^- channels and release of the organic osmolyte taurine, major components of regulatory cell volume decrease. However, ras oncogene activation leads to activation and CD95 receptor triggering to inhibition of K⁺ channels. The effects counteract the respective cell volume changes. Presumably, they serve to regulate cell membrane potential, which is decisive for Ca⁺⁺ entry through I_CRAC and the generation of cytosolic Ca⁺⁺ oscillations in proliferating cells. As a matter of fact I_CRAC is activated in ras oncogene expressing cells and inhibited in CD95-triggered cells. Activation of K⁺ channels and Na⁺/H⁺ exchanger as well as Ca⁺⁺ oscillations have been observed in a wide variety of cells upon exposure to diverse mitogenic factors. Conversely, diverse apoptotic factors have been shown to activate Cl^- channels and organic osmolyte release. Inhibition of K⁺ channels is apparently, however, not a constant phenomenon paralleling apoptosis which in some cells may even require the operation of K⁺ channels. Moreover, cell proliferation may at some point require activation of Cl^- channels. In any case, the alterations of cell volume are obviously important for the outcome, as cell shrinkage impedes cell proliferation and apoptosis can be elicited by increase of extracellular osmolarity. At this stage little is known about the interplay of cell volume regulatory mechanisms and the cellular machinery leading to mitosis or death of the cell. Thus, considerable further experimental effort is required in this exciting area of cell physiology.

TMEM16 Proteins Produce Volume-regulated Chloride Currents That Are Reduced in Mice Lacking TMEM16A

“…Cell Culture, cDNAs, and Transfection-Cell lines from human embryonic kidney (HEK293), human colon carcinoma (HT 29 ), and human cystic fibrosis pancreatic epithelial (CFPAC) cells were cultured as described (22). cDNA for mouse TMEM16B was purchased from ImaGenes GmbH (Berlin, Germany; clone name IRAVp968H1167D).…”

Cellular changes in boric acid-treated DU-145 prostate cancer cells

“…We believe the DU-145 cell line is responding to higher concentrations of BA by rearranging its cell shape into a flattened, low-volume state ( Figure 3A). These structural alterations in shape and size are likely contributing to the inability of the cells to proliferate, since increased cell volume and a rounding up from the attached substrate are both critical events during mitotic division (Lang et al, 2000;Fujibuchi et al, 2005). The observation that morphological alterations did not appear following 1 and 2 day BA exposures, but did at 8 days, argues the changes reflect secondary response of long-term treatment with BA.…”

The Src Family Kinase Yes Triggers Hyperosmotic Activation of the Epidermal Growth Factor Receptor and CD95

“…Changes in liver cell hydration are important regulators of hepatic metabolism, gene expression, and transport across the plasma membrane through activation of osmosensing and osmosignaling pathways (1)(2)(3)(4)(5)(6). Hypoosmotic cell swelling involves integrin-dependent osmosensing and osmosignaling via Src kinase and mitogen-activated protein kinases (7,8), resulting in an inhibition of autophagic proteolysis and stimulation of bile acid excretion (7,8).…”

“…Apart from effects on metabolism and gene expression (1)(2)(3)(4)(5)(6), hyperosmotic hepatocyte shrinkage triggers a rapid translocation of intracellular CD95 to the plasma membrane, which is accompanied by DISC 1 formation and sensitizes hepatocytes toward CD95 ligand (CD95L)-induced apoptosis (9,10). Hyperosmotic membrane targeting and activation of CD95 involves rapid activation of the epidermal growth factor receptor (EGFR) and of c-Jun-N-terminal kinases (JNK) (10), an association of activated EGFR and CD95, and subsequent CD95 tyrosine phosphorylation by the EGFR tyrosine kinase activity.…”