Potential and proliferation. In a normal, nonproliferating cell, the resting membrane potential (Vm ≈ −50 mV) is set by ion channel activity. Phosphatidylserine lipids are in small clusters that localize with K-Ras, which leads to low activation of the RAF-MAPK pathway. Channel overexpression depolarizes the cell (Vm ≈ −10 mV), increasing the clustering of phosphatidylserine and K-Ras. This promotes RAF-MAPK signaling uncontrolled cell proliferation.
Scientists discover electrical control of cancer cell growth
【LWBS 2015 08 26 A】(SpringRain Edited from Science)
The molecular switches regulating human cell growth do a great job of replacing cells that die during the course of a lifetime. But when they misfire, life-threatening cancers can occur. Research led by scientists at The University of Texas Health Science Center at Houston (UTHealth) has revealed a new electrical mechanism that can control these switches.
This information is seen as critical in developing treatments for some of the most lethal types of cancer including pancreatic, colon and lung, which are characterized by uncontrolled cell growth caused by breakdowns in cell signaling cascades.
The research focused on a molecular switch called K-Ras. Mutated versions of K-Ras are found in about 20 percent of all human cancers in the United States and these mutations lock the K-Ras switch in the on position.
"When K-Ras is locked in the on position, it drives cell division, which leads to the production of a cancer," said John Hancock, M.B., B.Chir, Ph.D., ScD, the study's senior author and chairman of the Department of Integrative Biology and Pharmacology at UTHealth Medical School. "We have identified a completely new molecular mechanism that further enhances the activity of K-Ras."
Findings appear in Science, a journal of the American Association for the Advancement of Science.
The study focused on the tiny electrical charges that all cells carry across their plasma membrane. "What we have shown is that the electrical potential (charge) that a cell carries is inversely proportional to the strength of a K-Ras signal," Hancock said.
With the aid of a high-powered electron microscope, the investigators observed that certain lipid molecules in the plasma membrane respond to an electrical charge, which in turn amplifies the output of the Ras signaling circuit. This is exactly like a transistor in an electronic circuit board.
Yong Zhou, Ph.D., first author and assistant professor of integrative biology and pharmacology at UTHealth Medical School, said, "Our results may finally account for a long-standing but unexplained observation that many cancer cells actively try to reduce their electrical charge."
Initial work was done with human and animal cells and findings were subsequently confirmed in a fruit fly model on membrane organization.
"This has huge implications for biology," Hancock said. "Beyond the immediate relevance to K-Ras in cancer, it is a completely new way that cells can use electrical charge to control a multitude of signaling pathways, which may be particularly relevant to the nervous system."
“The study provides a long-awaited mechanism by which membrane voltage directly affects the cell division cycle, a breakthrough that should pave the way for developing strategies that silence oncogenic pathways.” Alessio Accardi, PhD，an assistant professor of Biochemistry at Weill Cornell Medical College commented on Science.
The human genes encoding H-, N-, and K-Ras are among the most commonly occurring mutated oncogenes. Mutations that constitutively activate K-Ras are found in nearly 25% of all human tumors. Positively charged residues in the C termini of Ras proteins interact with negatively charged lipids that sequester these proteins into spatially localized assemblies called nanoclusters. Such aggregation is essential for K-Ras–induced activation of the RAF–mitogen-activated protein kinase (MAPK) cascade.
Using an elegant combination of electron microscopy, electrophysiological recordings, and fluorescence imaging, Zhou et al. show that membrane depolarization specifically and reversibly promotes clustering of two types of negatively charged lipids, phosphatidylserine and phosphatidylinositol 4,5-bisphosphate (PIP2). Upon depolarization, nanoclustering of phosphatidylserine and K-Ras increased with closely matching spatiotemporal and voltage dependencies. This activated the RAF-MAPK cascade, thereby promoting cell proliferation. By contrast, hyperpolarizing potentials had the opposite effect of reducing phosphatidylserine and K-Ras clustering and decreasing RAF-MAPK signaling.
Interestingly, the observed effects are highly specific in that only the distribution of phosphatidylserine and PIP2 is affected by membrane voltage, whereas that of other anionic lipids, such as phosphatidic acid or phosphatidylinositol 3,4,5-trisphosphate (PIP3), are unaffected. Similarly, K-Ras, unlike H- or N-Ras, responds to changes in phosphatidylserine distribution. The high selectivity of these effects among different Ras isoforms and similarly charged lipids could allow for the development of specifically targeted therapies. However, the molecular bases underlying the specificity of these effects remain unclear, and other unidentified proteins might be involved in these processes.