AP-1: a keymaster FOStering the JUNction among several tissues by wERKing on the cellular MAPk

AP-1: ID and biological functions

AP-1 (Activator Protein-1) is a transcription factor that plays a key role in regulating gene expression involved in a wide range of cellular processes, including proliferation, apoptosis, differentiation and stress response. AP-1 is a protein complex composed mainly of members of the Fos (c-Fos, FosB, Fra-1, Fra-2) and Jun (c-Jun, JunB, JunD) protein families, which bind together to form homodimers or heterodimers to bind to specific DNA sequences known as AP-1 response elements (TREs or AREs). AP-1 is involved in the regulation of genes that influence many cellular functions. For example, it is crucial for the expression of cytokines, chemokines and other inflammatory molecules. This makes it important for innate and adaptive immune responses. AP-1 controls cell growth and differentiation, especially in tissues such as the skin and the nervous system. AP-1 is also activated by stimuli such as oxidative stress and inflammation, facilitating the expression of genes involved in cellular protection. Alterations in AP-1 activity are often associated with cancer, as its upregulation can promote cell proliferation and tumor invasion.

Roles of AP-1 in the brain

AP-1 transcription factor plays a crucial role in neuronal homeostasis and functions, affecting processes such as neuronal survival, differentiation, synaptic plasticity, and response to stress. For example, c-Fos and c-Jun are essential for neuronal differentiation processes such as neurite outgrowth. AP-1 regulates the expression of genes required for the maturation and specialization of neurons, guiding axon and dendrite formation. In this context, AP-1 contributes to the establishment of synaptic connections that are crucial for neuronal network formation during brain development. Studies have shown that AP-1 is activated by neurotrophins (e.g., nerve growth factor, NGF) through the MAPK signaling pathway, which leads to the transcription of genes important for neuron survival and differentiation. In addition, AP-1 plays a critical role in synaptic plasticity, the ability of synapses to strengthen or weaken over time, which is essential for learning and memory. AP-1 regulates the expression of proteins involved in long-term potentiation (LTP) and long-term depression (LTD), processes that underlie memory formation. For instance, c-Fos expression is rapidly induced following neuronal activity, and it is thought to regulate synaptic strength by controlling the transcription of genes involved in synaptic growth and reorganization.

Role in neurodegenerative diseases

AP-1 is involved in the regulation of neuronal survival and apoptosis, depending on the composition of the AP-1 complex and the signaling context. For example, c-Jun is essential for stress responses in neurons, where it can promote both survival and apoptosis. Under normal physiological conditions, c-Jun promotes neuronal survival by inducing the expression of survival genes. However, during injury or neurodegenerative conditions, sustained activation of c-Jun can lead to apoptosis through the activation of pro-apoptotic genes such as Bim and PUMA. AP-1 is a key player in the neuronal response to oxidative stress, which is critical for protecting neurons from damage and maintaining homeostasis. Oxidative stress activates AP-1 through pathways like the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways.

 In neurons, AP-1 controls the expression of antioxidant enzymes such as superoxide dismutase (SOD) and other molecules that mitigate oxidative damage, thereby preventing neurodegeneration. Dysregulation of AP-1 activity is implicated in several neurodegenerative diseases, including Alzheimer’s disease (ALD), Parkinson’s disease (PAD), and Huntington’s disease (HUD). In these conditions, chronic activation of AP-1, particularly through the JNK pathway, can contribute to neuronal death and exacerbate disease progression. For example, increased c-Jun activation is observed in ALD and PAD, where it is associated with apoptotic pathways and neuroinflammation.

AP-1 in oncogenesis and cancer development

AP-1 is critically involved in controlling cell proliferation by regulating the expression of genes that drive the cell cycle. It promotes the expression of genes like cyclin D1, which is essential for the transition from the G1 to S phase of the cell cycle. Overactivation of AP-1, particularly through c-Jun and c-Fos, is associated with increased cellular proliferation, which is a hallmark of cancer. AP-1 also contributes to the survival of cancer cells by regulating the expression of anti-apoptotic genes such as Bcl-2, thereby preventing programmed cell death and promoting the survival of malignant cells. Studies have shown that AP-1 activation, particularly through the MAPK/ERK signaling pathway, leads to increased expression of cyclin D1, which drives uncontrolled cell division in several cancers, including breast and lung cancers.

AP-1 plays a central role in the regulation of genes involved in cell migration and invasion, processes essential for metastasis. It regulates the expression of matrix metalloproteinases (MMPs), particularly MMP-1, MMP-9, and MMP-13, which degrade the extracellular matrix, facilitating the invasion of cancer cells into surrounding tissues and their dissemination to distant organs. AP-1 also regulates integrins and cell adhesion molecules, further promoting cancer cell migration. Tumor angiogenesis, the formation of new blood vessels to supply oxygen and nutrients to tumors, is another key process regulated by AP-1. It promotes the expression of vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis, by binding to its promoter region.

AP-1 inhibitors from natural sources

In recent years, natural products have been explored as potential inhibitors of AP-1, as overactivation of this transcription factor is linked to several chronic diseases, including cancer, inflammation, and autoimmune diseases. Here are some natural inhibitors that have been studied for their ability to modulate AP-1 activity:

1. Curcumin: extracted from Curcuma longa, curcumin is a powerful antioxidant and anti-inflammatory. Numerous scientific studies have shown that curcumin has a broad spectrum of anti-tumor activity, with effects on several types of cancer, including breast, colon, prostate, and lung. Curcumin has been shown to inhibit the proliferation of tumor cells by interfering with cell division cycles. It works by blocking specific cyclin-dependent kinases (CDKs) and arresting tumor cells in different phases of the cell cycle, particularly in the G2/M phase. It is known to inhibit AP-1 activation by blocking the signaling cascade that leads to its activation, such as the ERK/MAPK (Mitogen-Activated Protein Kinase) pathway, which regulates AP-1 activity.
2. Resveratrol: found in grapes, nuts (especially peanuts) and berries, this polyphenol is known for its antioxidant and anti-inflammatory properties. Resveratrol has been shown to be particularly effective in prostate, breast, liver, colon, and lung cancer. Resveratrol is able to inhibit AP-1 by interfering with the activation of ERK1/2 (MAPK), which in turn affects AP-1 activity.
3. Epigallocatechin gallate (EGCG): a major polyphenol found in green tea, several studies have shown that EGCG can inhibit the growth of prostate cancer by inducing apoptosis and cell cycle arrest. It has a similar effect on breast, liver and lung cancer cells. EGCG inhibits AP-1 by modulating the MAPK signaling pathway and reducing the levels of c-Jun phosphorylation. It also inhibits the PI3K/Akt/mTOR pathway, which is crucial for the survival and proliferation of tumor cells.
4. Quercetin: a flavonoid very represented in apples, red onions, propolis, parsley, sage, eggplant skin and dark berries. Several studies have shown that quercetin can inhibit the growth of prostate cancer cells. This effect is mediated in part by inhibiting the androgen signaling pathway. It reduces the proliferation of breast cancer cells by modulating the cell cycle and inducing apoptosis. Finally, quercetin has also been studied for its effectiveness in lung cancer. Studies suggest that it reduces tumor growth and the ability of tumor cells to invade surrounding tissue. One way it does this is by inhibiting the activation of AP-1 by reducing the phosphorylation of its Jun and Fos components, which delays their ability to form active complexes and bind to DNA.
5. Betulin and betulinic acid. Triterpene compounds isolated from Betula alba (white birch), are known for their antitumor properties. Betulinic acid was originally discovered for its activity against human melanoma. Subsequently, it was shown to also act on lung, brain (glioblastoma) and colon cancer. It works by blocking tumor cells in certain phases of the cell cycle, such as the G1 or G2/M phase, preventing them from dividing and proliferating. This block is mediated by the negative regulation of proteins involved in the cell cycle, such as cyclin-dependent kinases (CDK). Betulin and betulinic acid have shown the ability to inhibit AP-1, inhibiting the signals that control its activation, such as the MAPK pathway.
6. Boswellia serrata (boswellic acid): isolated from the frankincense plant, boswellic acids inhibit the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2), which are involved in the synthesis of leukotrienes and prostaglandins, which are pro-inflammatory molecules associated with tumor growth. Since many tumors exploit chronic inflammation to grow and spread, inhibition of these enzymes by boswellic acids reduces tumor-associated inflammation and, consequently, the proliferation of cancer cells. Boswellic acids inhibit AP-1 activity by suppressing the transcription of genes involved in inflammation, such as TNF-α and IL-1β. They have been shown to be active against colon, pancreatic, prostate and brain cancers and lymphomas.
7. Celastrol: derived from the plant Tripterygium wilfordii, celastrol has anti-inflammatory and anti-cancer properties. Celastrol has demonstrated anti-tumor effects in several types of cancer, including melanoma, lung cancer, breast cancer, and prostate cancer. Its anti-tumor properties arise from its ability to induce apoptosis in tumor cells and inhibit cell proliferation by modulating growth factors and oncogenic signaling pathways. It is known to block the activation of AP-1, inhibiting the MAPK signaling cascade and reducing the ability of AP-1 to bind to DNA.

Therapeutic applications

Natural product-derived AP-1 inhibitors are of great interest for the treatment of diseases related to its excessive activation, such as cancer, chronic inflammatory diseases and autoimmune diseases. These compounds can act as modulators of cellular signaling, reducing the expression of genes associated with pathological processes. In conclusion, AP-1 represents a key target in pharmacological therapy, and many natural compounds show promising ability to inhibit its activity, offering potential therapeutic strategies for diseases in which AP-1 is overactivated. Unfortunately, most of these natural substances suffer with defects in bioavailability, which has been found discrepant by comparing in vitro, in vivo and natural settings. This is why basic science is aiming toward synthetic small molecules having better oral availability, stability, pharmacokynetc and longer half-life.

• edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

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