Dresden researchers discover resistance mechanism in aggressive cancer: Protease blocks guardian function against uncontrolled cell division

Researchers of the Carl Gustav Carus University Hospital Dresden at the National Center for Tumor Diseases Dresden (NCT/UCC), together with an international team of researchers, have deciphered a previously unknown survival mechanism in the nucleus of particularly aggressive tumor cells. Accumultion of the protein-cleaving enzyme (protease) caspase 8, in the nucleus of particularly aggressive cancer cells, plays an important role here. If the enzyme could be chemically inhibited at this point, it might be possible to effectively combat various types of cancer, even in advanced progression stages. The discovery of the mechanism therefore offers a promising approach for the development of new targeted therapies. In addition to pigment cell-derived skin cancer (malignant melanoma) and prostate tumors, the corresponding mechanism has been suggested for other tumor types, including pancreatic cancer, bladder cancer, breast cancer, colon cancer, ovarian cancer, testicular cancer, lung cancer, kidney cancer and brain tumors. The results of the study were published today, Wednesday (22nd January 2020), on the website of the journal "Molecular Cell" (www.cell.com, DOI 10.1016/j.molcel.2019.12.023).

Tumor cells usually proliferate particularly rapidly, overriding control mechanisms with which the body tries to prevent the division of damaged cancerous cells. Mutations in the nuclear p53 protein, the “guardian of the genome” play a crucial role in cancer cell progression. However, especially in aggressive cancer cells of the metastatic diseases such as malignant melanoma, p53 is mostly present in its normal, non-mutated and therefore functional form. Nevertheless, it obviously cannot fulfil its function as the guardian. This is due to a previously unknown mechanism that causes the p53 level in the nucleus of aggressive cancer cells to be too low to drive damaged cancer cells into programmed cell death - a cell suicide programme.

An important role in this mechanism is played by the enzyme caspase 8, which normally only occurs in the cytoplasm - the basic substance of the cell surrounding the cell nucleus - but accumulates in the cell nucleus of aggressive cancer cells. "We were able to show for the first time that caspase 8 cleaves a special protein - USP28 - in the nucleus, which is responsible for the accumulation of p53 levels in cancer cells with increased DNA damage. As a result, p53 continues being degraded and can no longer perform its control function. Cells with damaged DNA are no longer driven into a programmed cell death, but are directed to cell division instead," explains Prof. Dagmar Kulms, head of the "Experimental Dermatology" department of the Carl Gustav Carus University Hospital Dresden at the National Center for Tumor Diseases Dresden (NCT/UCC). "The effectiveness of this mechanism is shown by the poor survival rates of patients in whom an accumulation of caspase 8 in the nucleus of tumor cells can be detected. It is precisely these cells that are often also found in large numbers of relapsed tumor mass, which in many aggressive cancers eludes initial successful treatment," says Dr. Mads Daugaard of the Vancouver Prostate Centre (Canada).

The researchers were able to prove the mechanism in the laboratory using numerous cell lines and patient tissue for malignant melanoma and prostate cancer. Investigations on cell lines of other tumor types, including pancreatic cancer, bladder cancer, breast cancer, colon cancer, ovarian cancer, testicular cancer, lung cancer, kidney cancer and brain tumors, could confirm the mechanism.
It is particularly promising that caspase 8 only occurs in the nucleus of aggressive cancer cells, where it cleaves the protein USP28. If it was possible to inhibit the interaction of caspase 8 and USP28 with a chemical compound, the aggressive tumor cells could selectively be combated in the future. "Ideally, this could possibly lead to the inhibition of the proliferation and outgrowth of metastatic cancers for which current tumor therapies fail. The mechanism plays a role in a large number of cancers. Therefore, our results are of particularly high clinical relevance," says Prof. Stefan Beissert, Director of the Department of Dermatology at the University Hospital Dresden. Together with specialised chemists, the researchers intend to conduct research on a corresponding active substance in the future.

Publication
Ines Müller, Elwira Strozyk, Sebastian Schindler, Stefan Beissert, Htoo Zarni Oo, Thomas Sauter, Philippe Lucarelli, Sebastian Raeth, Angelika Hausser, Nader Al Nakouzi, Ladan Fazli, Martin E. Gleave, He Liu, Hans-Uwe Simon, Henning Walczak, Douglas R. Green, Jiri Bartek, Mads Daugaard and Dagmar Kulms: Cancer cells employ nuclear caspase-8 to overcome the p53-dependent G2/M checkpoint through splitting USP28
Molecular Cell DOI 10.1016/j.molcel.2019.12.023

Two images in printable resolution are available for the press release:
https://www.nct-dresden.de/fileadmin/media/nct-dresden/das-nct/newsroom/Bild1_PM_Caspase8.jpg
Caption 1: View into tumor tissue of malignant melanoma: The enzyme caspase 8 (dark red dots) accumulates in the nuclei of the cancer cells and activates the cell survival mechanism, which is fatal for patients.
https://www.nct-dresden.de/fileadmin/media/nct-dresden/das-nct/newsroom/Bild2_PM_Caspase8.JPG
Caption 2: A newly discovered mechanism shows how the enzyme caspase 8 at the so-called G2/M damage control point blocks the guardian function of the protein p53,
prevents programmed cell death, and instead directs the damaged cancer cells into cell cycle progression.

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