In an article that is being published today as an advanced online publication by the journal Nature, the researchers say the growth-stimulating molecule called p110beta -- part of a cellular signaling network disrupted in several common cancers -- is a promising target for novel cancer therapies designed to shut it down. The report's lead authors are Shidong Jia, MD, PhD, Zhenning Liu, PhD, Sen Zhang PhD, and Pixu Liu, MD, PhD.
The p110beta molecule and a counterpart, p110alpha, are "isoforms" -- slightly different forms – of an enzyme called PI(3)K that is an intense focus of cancer research and drug development. PI(3)K is the linchpin of a cell-signal pathway that responds to growth factor signals from outside the cell.
When activated by growth factor receptors, PI(3)K turns on a cascade of genes and proteins that drives cells to divide and grow. The molecular accelerator is normally kept under control by a tumor-suppressor protein, PTEN, which acts like a brake to curb excess cell growth that could lead to cancer.
Mutations that inactivate PTEN -- in effect releasing the brake on growth signals -- are found in a significant proportion of prostate, breast and brain tumors. The senior authors of the new report, Jean Zhao, PhD, and Thomas Roberts, PhD, previously showed that blocking p110alpha protein inhibits cancerous growth induced by various cancer-causing proteins, such as Her2 and EGFR. With that knowledge in hand, the researchers, in collaboration with pharmaceutical companies, are developing p110alpha blockers.
P110beta, by contrast, was thought to be a relatively insignificant player in tumors. However, "the surprise in this paper is that p110beta has been found to be a bigger player than p110alpha in tumors that result from PTEN loss," noted Zhao. "Now the drug companies, which have been focusing on p110alpha, will have to think about making p110beta inhibitors as well."
Both forms of the p110 molecule have dual tasks: they are involved in responding to insulin signals -- a metabolic function -- as well as relaying growth signals from outside the cell. But the importance of 110beta had been vastly underestimated, the researchers said, for reasons they don't entirely understand.
"We knew that when cells are stimulated with growth factor signals, the activity of p110alpha, but not p110beta, rises rapidly and sharply in triggering excess cell growth," Zhao said. "We speculate that 110beta may be providing a low-level but steady growth stimulus and when PTEN is lost, it becomes an important source of cell proliferation signals."
The new findings stem from experiments in which the scientists disabled the p110beta protein in mice as a way of exploring its normal functions. In one of the experiments, the researchers "knocked out" p110beta in mice that also lacked the PTEN tumor suppressor protein and were therefore highly prone to prostate cancer. Mice that lacked PTEN but had functioning p110beta proteins all developed early prostate cancers by 12 weeks of age. In contrast, the "knockout" mice with no p110beta function remained free of prostate cancer even though the PTEN "brake" had been disabled.
The scientists concluded, as a result, that p110beta becomes a "powerhouse" to drive cancerous cell growth when PTEN function is missing.
In light of the new findings, there is likely to be great interest in finding drugs or other tools to block the p110beta protein in cancers where mutations in PTEN have unleashed the overactive growth signals, said Zhao, who is also an assistant professor of surgery at Harvard Medical School.
The task is made somewhat easier, said Roberts, by the fact that "we know what the inhibitor should look like because of our work on p110alpha inhibitors."
Roberts, who is also a professor of pathology at Harvard Medical School, said that drugs designed to block the p110alpha form are on their way to clinical testing, but he could not predict when p110beta inhibitors might become available for clinical testing.
Solving the efficiency of Gram-negative bacteria
22.03.2019 | Harvard University
Bacteria bide their time when antibiotics attack
22.03.2019 | Rice University
DESY and MPSD scientists create high-order harmonics from solids with controlled polarization states, taking advantage of both crystal symmetry and attosecond electronic dynamics. The newly demonstrated technique might find intriguing applications in petahertz electronics and for spectroscopic studies of novel quantum materials.
The nonlinear process of high-order harmonic generation (HHG) in gases is one of the cornerstones of attosecond science (an attosecond is a billionth of a...
Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.
The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...
Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.
Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
22.03.2019 | Life Sciences
22.03.2019 | Life Sciences
22.03.2019 | Information Technology