In cancer and developmental brain disorders, certain anchor proteins play an important role in inhibiting a key metabolic driver. This molecular mechanism can open new opportunities for personalized therapies for cancer and neuronal diseases.
The research conducted by scientists from the German Cancer Research Center (DKFZ) and the University of Innsbruck, together with a Europe-wide research network is published in the journal Cell.
The signaling protein known as MTOR (Mechanistic Target of Rapamycin) is a sensor for nutrients like amino acids and sugars. When sufficient amount of nutrients are available, MTOR boosts metabolism. It also makes sure that sufficient energy and cellular building blocks are available. Hence, MTOR is a central switch for metabolism and any errors in its activation can lead to serious diseases such as cancers. It can also lead to developmental disorders of the nervous system resulting in behavioral disorders. If MTOR is malfunctioning, it can also result in epilepsy.
The scientists investigated how the TSC complex binds to lysosomes and it was found that G3BP proteins (Ras GTPase-activating protein-binding protein) that are located with the TSC complex on lysosomes, perform the function of an anchor that ensures that the TSC complex can bind to the lysosomes.
In breast cancer cells, this anchor function plays an important role. If the amount of the anchor G3BP proteins reduces in the cell culture, then an increase in the MTOR activity and cell migration is seen.
The scientists were able to show in cell cultures that drugs that inhibit this MTOR, can prevent the spread of cancer. Especially in breast cancer, low levels of G3BP indicate a poor prognosis.
Kathrin Thedieck, professor of biochemistry at the University of Innsbruck said, "Markers like the G3BP proteins could be helpful to personalize therapies based on inhibition of MTOR."
Drugs that block MTOR are already approved as anti-cancer drugs. These drugs could be tested specifically in furture studies.
In the brain, G3BP proteins were able to inhibit MTOR. The scientists observed disturbances in brain development when G3BP is absent in zebrafish which is an important animal model. These disturbances resulted in neuronal hyperactivity similar to epilepsy in humans. Drugs that inhibit MTOR can suppress this neuronal discharges.
Christiane Opitz of DKFZ said, " We therefore hope that patients with rare hereditary neurological diseases in which dysfunctions of the G3BP proteins play a role could benefit from drugs against MTOR."
The scientists plan to investigate this further with their Europe-wide research network.