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p73 engages A2B receptor signalling to prime cancer cells to chemotherapy-induced death
J S Long1, P M Schoonen1,2, D Graczyk1
1Cancer Research UK Beatson Institute, Glasgow, UK.
Abstract:
Tumour cells often acquire the ability to escape cell death, a key event leading to the development of cancer. In almost half of all human cancers, the capability to induce cell death is reduced by the mutation and inactivation of p53, a tumour suppressor protein that is a central regulator of apoptosis. As a result, there is a crucial need to identify different cell death pathways that could be targeted in malignancies lacking p53. p73, the closely related p53 family member, can regulate many p53 target genes and therefore some of the same cellular responses as p53. Unlike p53, however, p73 is seldom mutated in cancer, making it an attractive, alternative death effector to target. We report here the ability of p73 to upregulate the expression of the A2B receptor, a recently characterized p53 target that effectively promotes cell death in response to extracellular adenosine--a metabolite that accumulates during various forms of cellular stress. Importantly, we show that p73-dependent stimulation of A2B signalling markedly enhances apoptosis in cancer cells that are devoid of p53. This mode of death is caspase- and puma-dependent, and can be prevented by the overexpression of anti-apoptotic Bcl-X(L). Moreover, treatment of p53-null cancer cells with the chemotherapeutic drug adriamycin (doxorubicin) induces A2B in a p73-dependent manner and, in combination with an A2B agonist, substantially enhances apoptotic death. We therefore propose an alternate and distinct p53-independent pathway to stimulate programmed cell death involving p73-mediated engagement of adenosine signalling.
Insights
Cancer cells evade death by inactivating the p53 protein. This study reveals a p53-independent pathway using p73 to activate the A2B receptor, promoting cancer cell death, offering new therapeutic targets.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Death Pathways
Background:
- Tumor cells frequently evade apoptosis, a crucial step in cancer development.
- Mutations inactivating the p53 tumor suppressor protein are common in human cancers, reducing apoptosis.
- Targeting alternative cell death pathways is vital for treating p53-deficient cancers.
Purpose of the Study:
- To identify and characterize p53-independent cell death pathways for cancer therapy.
- To investigate the role of p73 in regulating apoptosis in p53-null cancer cells.
- To explore the potential of targeting the A2B receptor and adenosine signaling in cancer treatment.
Main Methods:
- Investigated p73's ability to upregulate the A2B receptor expression.
- Assessed the effect of p73-mediated A2B signaling on apoptosis in p53-null cancer cells.
- Examined the role of caspases, PUMA, and Bcl-X(L) in this cell death pathway.
- Evaluated the combined effect of adriamycin and an A2B agonist on apoptosis in p53-null cancer cells.
Main Results:
- p73 upregulates the expression of the A2B receptor, a p53 target gene.
- p73-dependent A2B signaling significantly enhances apoptosis in p53-null cancer cells.
- This apoptosis is dependent on caspases and PUMA, and inhibited by Bcl-X(L).
- Adriamycin treatment induces A2B in a p73-dependent manner, and its combination with an A2B agonist increases apoptosis.
Conclusions:
- p73 activation of A2B receptor signaling provides a p53-independent pathway to induce apoptosis.
- This pathway represents a novel therapeutic strategy for p53-deficient cancers.
- Targeting adenosine signaling via p73 and A2B offers a promising approach for cancer treatment.
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