AN unbalanced relationship between two proteins rapidly triggers the tumor process. The two proteins, both involved in the cell division process, are Amber1 and Cycline D and the former is the switch of the latter. When the switch doesn’t work well, when it doesn’t turn on and off as and when it should, so many types of cancer – lung adenocarcinoma, sarcoma and glioblastoma for example – kick in fast. A study conducted by researchers from the Bambino Gesù Pediatric Hospital in collaboration with the University of Rome Tor Vergata and other European and American research centers says that Ambra1 controls Cycline D and has just been published on Nature together with two other international papers arriving at the same conclusion. The discovery may pave the way for new possibilities for cancer treatment, as well as adding to the knowledge of how the cell cycle works in diseased cells.
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The cell cycle is the process that leads a cell to divide in two and proliferate and is regulated by Cycline, a group of proteins classified with the letters A, B, C, D etc. Each of these molecules does a piece of the work and all are produced and destroyed in a precise sequence, until two daughter cells are formed from a parent cell. During the process of division, the genes that control the cell cycle can undergo mutations, which can accumulate and give rise to tumors. These mutations develop during the replication of the DNA, which in a specific phase of the cycle duplicates itself to be transferred to the daughter cells. Well, cyclin D is precisely the molecule that regulates DNA replication, and until now its mechanism of action was not known.
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An inordinate replication
The study that led to the discovery of the correlation between the Amber1 and Cycline D proteins was led by Francesco Cecconi Professor of Developmental Biology at the University of Rome Tor Vergata and researcher of the Child Jesus. The researchers started from the intuition of a possible role of Ambra1 in some defects of the cell cycle and worked on hundreds of samples: animal models, cells in culture, cells derived from both animal and human tumors, using imaging techniques, microscopy, fluorescence, genetic engineering, biochemistry, histology. During the investigations, the authors of the paper noted that when Ambra1 is absent or present in limited quantities, Cycline D is not destroyed as it should but accumulates. “This accumulation – explains Cecconi – causes the cells to divide at an exaggerated speed, and more daughter cells are formed in a shorter time. During this excessive replication – the researcher continues – DNA accumulates errors and this favors the development of tumors. But today there are no drugs available that can act directly on the Amber1 and Cycline D proteins to restore the right amount “. Then? “So we found an alternative solution: we inhibited the DNA repair system, which is the self-defense mechanism present in all our cells. The meaning – says Cecconi – was to accumulate so many errors to lead cancer cells to self-destruction ”.
A mix of cancer drugs based on the Amber1-Cycline D imbalance
The research, in addition to representing an important step in the knowledge of cell replication mechanisms, and therefore also of the proliferation of tumor cells, opens up new perspectives in the treatment of tumors based on the Ambra1-CiclinaD imbalance. What drugs are we talking about? “We used a mix of drugs called repair system inhibitors, which worked: we saw that the cultured cells died and that the animals with cancer had a longer survival. The research, therefore, suggests that this treatment strategy, which has already been used for the treatment of some types of human cancer, can also be applied to patients with the altered Amber1 – Cycline D combination “
The Achilles heel
The idea, therefore, is that in patients diagnosed with cancer, the levels of Amber1 and Cycline D are also examined? “This is so – confirms Cecconi – and if the absence or low levels of Ambra1 were identified in the tumor cells in association with an accumulation of Cycline D, it could be possible to try to suppress the capacity of the tumor cells with specific drugs, already known in therapy. to repair the genetic material. If we could limit the repair, we could aim to kill cancer cells, exploiting their Achilles heel, that is their genomic instability which is the same that caused them to proliferate ”.
A new frontier in molecular oncology
“Our data also extends to cell proliferation processes in the developing nervous system – he adds Giacomo Milletti, research biologist of the Child Jesus, PhD student at the University of Rome “Tor Vergata” and first co-author of the study – and this new level of regulation could represent a new frontier in the molecular oncology of brain tumors in children “.
