Study reveals how Bcl-2 protein blocks cancer cell death

Researchers at Umeå University have contributed new insights into how cancer cells protect themselves from cell death. The study provides a deeper understanding of how key proteins interact within the cell and could, in the long term, support the development of new cancer therapies.

The findings, published in the journal ACS Chemical Biology, show how a central protein can block apoptosis – the process that normally causes cancer cells to die.

Apoptosis is a form of programmed cell death that plays a crucial role during embryonic development, in removing old or damaged cells, and in enabling the immune system to function properly. When apoptosis does not work as it should, as in many cancers, cells can divide uncontrollably and form tumours.

Many cancer treatments, such as chemotherapy and radiotherapy, work by causing damage or stress in cells that triggers apoptosis. However, many tumours manage to evade this form of cell death as well, making them resistant to treatment.

Blocking death-inducing proteins

One of the most important proteins controlling apoptosis is the cell‑killing protein Bax. Once activated, Bax can initiate apoptosis by forming pores in the membranes of mitochondria. Another key protein from the same family, the cell‑protective protein Bcl‑2, instead prevents Bax from killing harmful cells. In nearly half of all human cancers, one of the underlying problems is an increased production of Bcl‑2, which promotes tumour growth and often leads to poor response to therapy.

In our research, we have used advanced neutron experiments to show how Bcl‑2 protects cancer cells by blocking the death‑inducing proteins that are most often activated by therapy."

Gerhard Gröbner, professor at Umeå University and lead author of the study

The experiments show that Bcl‑2, which is located on the outer surface of the mitochondria, can capture and bind several Bax proteins at the same time. This makes the inhibition of cell death more efficient than previously thought. Cancer cells do not need to produce extremely large amounts of Bcl‑2 to protect themselves – even a moderate increase can be sufficient.

Opens up for new cancer treatments

The researchers also investigated how the composition of the mitochondrial membrane affects the interaction between the proteins. One particular lipid, cardiolipin, can promote apoptosis and help Bax form pores in the membrane. However, even in membranes containing cardiolipin, a sufficiently high level of Bcl‑2 can still prevent cell death.

"In the longer term, this type of knowledge could open up new opportunities for cancer treatment, for example by targeting Bcl‑2 and its protective function," says Gerhard Gröbner.

The study was carried out in collaboration between researchers from Umeå University, Lund University, the European Spallation Source (ESS) in Lund, the ISIS Neutron and Muon Source and Diamond Light Source in the United Kingdom, and the Institut Laue‑Langevin (ILL) in France.