Do you know what types of cancer are more likely to kill you? Do you know how to avoid contracting or how to treat these? Unfortunately, some cancers are more deadly than others, these tending to be the types whose course of disease is unpredictable, making their effective treatment rather unknown. Glioblastoma (GBM) is one such cancer, it being a lethal, malignant form of brain cancer that usually kills its host within 2 years if not less. Luckily though, recent research into how different cellular signaling pathways regulate tumor growth in GBM has shown promise in identifying ways to treat cancers like GBM. Here, we’ll discuss this topic and how regulating two molecules, the cAMP Response Element Binding Protein (CREB) and the BCL2-Like 11 (for short, “Bim”) protein, may fight the growth of cancer.
What Makes GBM So Complicated?
Part of what makes GBM, and other alike cancers, so hard to treat is that fact that are multiple types of GBM, and this impacts what the best course of treatment is. In addition, one type, called Neural GBM, has no obvious pattern when it comes to when genes it causes mutation to, making the survival rates of those with GBM very low. However, the fact that GBM causes mutations in a differing number of genes seems to be the common thread amongst all types.1
What Pathways May Be Involved in GBM
Figure 1. This illustrates how the MAPK, PI3K, and cAMP pathways regulate the activity of CREB, with asterisks indicating potential places for drug treatments.1
And these genes impact the expression of different pathways within neurons. With mesenchymal GBM, certain mutations lead to dysfunction of the mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K) pathways, which ultimately end up impacting what genes in a neuron are transcribed by regulating activity of cAMP Response Element Binding Protein (CREB), seen in Figure 1. CREB is called a transcription factor for this reason, and when its activity is upregulated in cases of GBM that disrupt the MAPK and PI3K pathways, is dysregulates the activity of typical proteins, causing tumor cell growth and irregular neuron development.1
Also seen in Figure 1 is how CREB activity is also regulated by the cyclic adenosine 3′,5′-monophosphate (cAMP) pathway. Opposite to the MAPK and PI3K pathways, cAMP has a low level of activation in tumor growths, so researchers hypothesize that elevating it would inhibit tumor growth.1 For more in-depth information on how treating different aspects of each pathway may degrade tumors, see [here].
The cAMP Pathway & Its Involvement in GBM
Figure 2. This displays the cAMP pathway and molecules, like Fsk, and PDEi, that would lead to its increased activation.1
Low cAMP levels are positively correlated with tumor malignancy, making it a promising target for cancer treatments. Research suggests that enzymes that work to activate cAMP, like forskolin (Fsk) and phosphodiesterase inhibitor (PDEi), would be effective.1 These are illustrated in Figure 2, and for more information on how they work, see [here].
But what makes the cAMP pathway cause tumor cell death? Well, research has shown that it may be due to its activity increasing the expression of Bim.
Bim & How it Impacts Tumor Growth in GBM
Figure 3. This displays the impact of stress signals on the expression of Bim proteins and their impact on the mitochondria.2
In mammals, Bim proteins directly interact with Bak and Bax, two pro-apoptotic proteins, meaning they induce cell death. They do this by increasing the mitochondrial outer membrane (MOM) permeability, demonstrated in Figure 3. This allows things to enter or exit the mitochondria that shouldn’t and initiates apoptotic pathways, thus causing cell death.2
Not only does expression of the Bim gene through its interaction with pro-apoptotic proteins, but it also acts to increase cell death by:
- Neutralizing the anti-apoptotic BCL-2 proteins, or…
- Uncoupling mitochondrial respiration, causing an increase in cellular levels of reactive oxygen species (ROSs).2
For more information on the pathways by which Bim works and what stimuli initiates its activation, see [here], and for a review on what the MOM does for the cell, watch this video: [MOM].3
How Bim Activation Can Be Used to Treat GBM
Bim typically is transcribed in response to certain stimuli independent of CREB, but in some cancer patients, the transcription of it and the creation of its Bim proteins may be decreased. So, if Bim levels can be increased in tumor cells, this may lead to their death in patients with GBM and alike cancers.2
Interestingly, the MAPK pathway inhibits Bim-regulated apoptosis as well, promoting tumor cell growth. So, Bim agonists may also be considered in GBM patients whose MAPK pathways are overly activated to induce tumor cell death.2
Conclusion
In conclusion, CREB activity is regulated by the PI3K, MAPK, and cAMP pathways, but the cAMP pathway’s activation of CREB leads to the creation/activation of proteins different than the MAPK and PI3K pathways. Therefore, if doctors and researchers can determine which pathway is disrupted in patients with GBM, they can administer treatment that directly targets the root of the problem, and this applies to all types of cancer. In the example of the cAMP pathway, it’s been shown that increased Bim expression leads to death of cancer cells, so in such patients where it is the cAMP pathway being disrupted, Bim activators may be effective treatments against GBM that don’t cause the side effects that a CREB inhibitor might, as Bim acts independently of CREB. Further research needs to be done on this topic, but ultimately, research on the genes involved in tumor cell growth provides a promising explanation as to why they occur and how we could possibly treat them without invasive treatments such as chemotherapy.
Footnotes:
1Fung, N.H, et. al. “Understanding and exploiting cell signaling convergence nodes and pathway cross-talk in malignant brain cancer.” Cellular Signaling, vol. 57, 2019, https://doi.org/10.1016/j.cellsig.2019.01.011
2Sionov, R.V., et. al. “Regulation of Bim in Health and Disease.” Oncotarget, vol. 6, no. 27, 2015, https://www.oncotarget.com/article/5492/text/
3Gauthier, Nicholas. “Outer Mitochondrial Membrane; Overview and Function.” Study.com, 2025, https://study.com/learn/lesson/video/outer-mitochondrial-membrane-function-layers-composition.html
