Researchers from the University of Texas Health Science Center at Houston have identified an electrical mechanism that controls one of the molecular switches regulating cell growth, and can cause multiple forms of cancer if it stops functioning properly.
The authors of the research, which is published in the journal Science, explained in a statement that their findings could lead to new treatments for some of the most lethal forms of the disease, including lung, colon, and pancreatic cancers. Those cancers, they noted, are all characterized by uncontrolled cell growth caused by breakdowns in cell signaling cascades.
Specifically, the research looked at a molecular switch known as K-Ras, mutated versions of which are found in roughly one-fifth of all human cancers in the US. Dr. John Hancock, senior author of the study, and his colleagues explained that the mutations lock this switch in the “on” position, driving the cell division process and leading to the production of cancer.
“A link between plasma membrane potential (the small amounts of electrical charge that can be measured across the limiting membrane of any cell) and tumor growth has been known since the 1970’s,” Dr. Hancock told redOrbit via email. “These early studies also showed that cells divide more rapidly if their plasma membrane potential is reduced.”
“As a strategy to treat cancer, many researchers therefore sought to restore normal membrane potential to cancer cells by inhibiting the operation of ion channels that generate this electrical charge,” he added. “However the fundamental question of why reducing plasma membrane potential should drive cancer cells to proliferate was unknown.”
K-Ras targeting drugs may have expanded cancer applications
Dr. Hancock’s team identified a new molecular mechanism through which electrical charges that are carried across the limiting or plasma membranes of cells enhance K-Ras activity. The charge carried by a cell is inversely proportional to the strength of the K-Ras signal, they noted.
Using a high-powered electron microscope, the researchers found that certain types of lipids in the plasma membrane respond to an electrical charge, which in turn amplifies the output of the Ras signaling circuit. Their findings could help account for widely known but not yet explained observations that many types of cancer cells actively attempt to reduce their electrical charge.
“Our new study shows that the crucial mechanistic link involves specific membrane lipids and the growth promoting oncogene K-Ras,” Dr. Hancock explained. “Our discovery suggests that drugs which target K-Ras may have much wider application in cancer than previously thought, and also that alternative therapeutic approaches to interfere with cellular lipids could have wide utility in cancer treatment.”
“The new discovery also has implications in neurological development because the same molecular conversion mechanism between membrane potential and cell growth and proliferation plays a key role in the brain processes that underlie learning and memory,” he added.
“Furthermore, it is still not clear how many voltage-dependent ion channels actually sense changes in membrane voltage. Our findings suggest a new lipid dependent, or lipid mediated mechanism whereby this may occur.”
Research part of the lab’s focus on cell growth mechanisms
Dr. Hancock told redOrbit that one of the primary focuses of his laboratory’s research program is to analyze the molecular mechanisms that regulate cell growth and proliferation, as well as how deviations to those mechanism can cause tumor development. Since K-Ras is mutated in some 90 percent of pancreatic cancer, 40 percent of colon cancer, and 35 percent of lung cancer cases, it was of particular interest to his team, he noted.
“Thus, we are interested in how K-Ras functions and how we can inhibit K-Ras as a strategy for cancer treatment,” the UT Health Science Center researcher said. “Studies from our group have previously shown that K-Ras needs to be attached to the inner plasma membrane in order for it to stimulate cell growth and proliferation. We also knew that K-Ras interacts with a very specific type of lipid on the plasma membrane called phosphatidylserine.”
“We therefore hypothesized that if the nanoscale organization of phosphatidylserine were sensitive to plasma membrane voltage then K-Ras function would also be impacted. We set out to systematically examine these ideas using various sophisticated imaging techniques including electron microscopy, which eventually led to the current discovery,” he added.
In a broader sense, Dr. Hancock said that his lab is interested in better understanding how the nanoscale spatial distributions (patterns of various signaling of proteins) the inner surface of a plasma membrane regulate their activity, and cell function as a whole.
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