How Cancer Cells Evade Chemotherapy-Induced Apoptosis

Researchers at Umeå University have provided new insights into how cancer cells defend themselves against cell death. The research offers a detailed understanding of how critical proteins interact inside the cell and may, over the long term, aid the development of new cancer treatments.

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The results, reported in the journal ACS Chemical Biology, demonstrate how a key protein can inhibit apoptosis, the process that typically causes cancer cells to die.

Apoptosis is a type of programmed cell death that is essential during embryonic development, in eliminating old or damaged cells, and in allowing the immune system to function correctly. When apoptosis fails to operate as it should, as seen in many cancers, cells can proliferate uncontrollably and form tumors.

Cancer therapies like chemotherapy and radiotherapy function by inducing damage or stress in cells that initiates apoptosis. However, numerous tumors are able to avoid this type of cell death as well, making them resistant to treatment.

Blocking Death-Inducing Proteins

One of the most critical proteins regulating apoptosis is the cell-killing protein Bax. Once activated, Bax can trigger apoptosis by creating pores in the mitochondrial membranes.

Another important protein from the same family, the cell-protective protein Bcl-2, instead blocks Bax from destroying harmful cells. In nearly half of all human cancers, one of the underlying issues is elevated production of Bcl-2, which drives tumor growth and often results in a 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, Study Lead Author and Professor, Umeå University

The experiments demonstrate that Bcl-2, which is present on the outer layer of the mitochondria, can capture and attach to multiple Bax proteins simultaneously. This makes the suppression of cell death more effective than was previously believed. Cancer cells do not require the production of extremely high amounts of Bcl-2 to defend themselves – even a moderate rise can be enough.

Opens Up for New Cancer Treatments

The researchers also examined how the composition of the mitochondrial membrane influences the interaction between the proteins. One specific lipid, cardiolipin, can enhance apoptosis and assist Bax in forming pores in the membrane. However, even in membranes that contain cardiolipin, a sufficiently high level of Bcl-2 can still inhibit 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.

Gerhard Gröbner, Study Lead Author and Professor, Umeå University