GO:1904102 cellular response to acadesine: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904102 describes the cellular response to acadesine (AICAR), an AMPK activator and adenosine analog [1, 2, 3].
• Acadesine triggers AMPK-dependent and AMPK-independent signaling, affecting proliferation, apoptosis, and metabolism.
• Key genes involved include PRKAA1/2 (AMPK), LATS1/2, BCL2, and PI3K/AKT pathway components [1, 2, 7].
• Acadesine shows anti-tumor activity in mantle cell lymphoma, myelodysplastic syndrome, and acute myeloid leukemia [1, 3, 8].
• CRISPR knockout, knock-in, and overexpression models are essential to dissect acadesine response pathways.
• EDITGENE provides custom cell models and screening services to study GO:1904102 in disease contexts.
Description
Acadesine (AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside) is a cell-permeable adenosine analog that elicits a complex cellular response, formally annotated as GO:1904102: cellular response to acadesine [1, 2]. This process encompasses changes in cell movement, secretion, enzyme production, and gene expression triggered by acadesine stimulation. Acadesine is widely used experimentally to activate AMP-activated protein kinase (AMPK) and to study metabolic stress responses. Its clinical potential has been explored in cardiovascular disorders and hematological malignancies [2, 5, 8]. Understanding the cellular response to acadesine is critical for researchers investigating energy homeostasis, apoptosis, and drug resistance. This article integrates QuickGO definition and verified PubMed literature to provide a research-grade overview of GO:1904102, its molecular players, and experimental strategies.
cellular response to acadesine At A Glance
| GO ID | GO:1904102 |
|---|---|
| GO term | cellular response to acadesine |
| Ontology | biological_process |
| Synonym | none |
| Major function | Cellular response to acadesine stimulus, including signaling, gene expression, and metabolic changes |
| Related stimuli | Acadesine (AICAR), an AMPK activator and adenosine analog |
| Key pathways | AMPK signaling, PI3K/Akt, LATS1/2 tumor suppressor pathway |
| Disease relevance | Mantle cell lymphoma, myelodysplastic syndrome, acute myeloid leukemia, cardiovascular inflammation |
What Is GO:1904102?
According to the Gene Ontology, GO:1904102 (cellular response to acadesine) is defined as any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an acadesine stimulus. This term is a biological process and has no synonyms in QuickGO. It captures the downstream cellular events triggered when a cell encounters acadesine, including signaling cascades, transcriptional changes, and metabolic adaptations [1, 2, 7].
Why Is cellular response to acadesine Important in Cell Biology?
GO:1904102 is important because acadesine is a widely used pharmacological tool to activate AMPK and to study cellular stress responses, and it has shown therapeutic potential in cancer and cardiovascular disease [1, 2, 3, 8]. Dissecting the cellular response to acadesine helps researchers understand how cells adapt to metabolic stress, how apoptosis is regulated, and how drug resistance emerges. Moreover, acadesine sensitizes Bcl-2-high mantle cell lymphoma cells to ABT-199 and circumvents azacitidine resistance in myeloid malignancies, highlighting its clinical relevance [1, 8].
• Acadesine activates AMPK, a central regulator of energy homeostasis.
• It induces apoptosis in cancer cells, including mantle cell lymphoma [1, 3].
• Acadesine inhibits tissue factor induction and thrombus formation via PI3K/Akt.
• It sensitizes Bcl-2-high lymphoma cells to BH3 mimetics like ABT-199.
• Acadesine circumvents azacitidine resistance in MDS and AML.
• It activates tumor suppressors LATS1 and LATS2 independently of AMPK.
• Acadesine modulates inflammatory responses in cardiopulmonary bypass.
• Adenosinergic drugs like acadesine are explored for cardiovascular disorders.
• It serves as a tool to study AMPK-independent signaling pathways.
• Understanding GO:1904102 aids in designing combination therapies for hematological malignancies [1, 3, 8].
What Happens During cellular response to acadesine?
Acadesine uptake and initial signaling
In simple terms: Acadesine enters the cell and starts to mimic AMP, triggering energy-sensing pathways.
Acadesine is taken up by cells and phosphorylated to ZMP, an AMP analog that activates AMPK. This initial step leads to downstream phosphorylation events, including activation of the PI3K/Akt pathway in endothelial cells. The cellular response begins with rapid changes in kinase activity and gene expression.
AMPK-dependent metabolic reprogramming
In simple terms: AMPK activation shifts the cell into energy-saving mode, affecting metabolism and growth.
Activated AMPK phosphorylates targets that inhibit anabolic processes and promote catabolic pathways. In mantle cell lymphoma, acadesine-induced AMPK activation contributes to anti-proliferative effects. This metabolic reprogramming is a hallmark of the cellular response to acadesine.
AMPK-independent activation of LATS1/2
In simple terms: Acadesine can also activate tumor suppressors without relying on AMPK.
Acadesine antiproliferative properties involve AMPK-independent activation of the tumor suppressors LATS1 and LATS2. This pathway adds complexity to the cellular response, showing that acadesine affects multiple signaling nodes beyond AMPK.
Apoptosis and cell cycle arrest
In simple terms: The cellular response often leads to cell death or growth arrest, especially in cancer cells.
Acadesine induces apoptosis in Bcl-2-high mantle cell lymphoma cells and sensitizes them to ABT-199. It also synergizes with rituximab in in vivo and in vitro models. These effects are mediated through mitochondrial apoptotic pathways and cell cycle checkpoints.
Modulation of thrombus formation and inflammation
In simple terms: Acadesine can reduce blood clotting and inflammation by affecting endothelial signaling.
Acadesine inhibits tissue factor induction and thrombus formation by activating the PI3K/Akt signaling pathway. This anti-inflammatory and anti-thrombotic response is part of the cellular response to acadesine in vascular cells [2, 4].
Key Genes Involved in GO:1904102 cellular response to acadesine
The following genes and proteins are central to the cellular response to acadesine, as supported by verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PRKAA1 | AMPK catalytic subunit alpha 1 | Mediates metabolic effects of acadesine |
| PRKAA2 | AMPK catalytic subunit alpha 2 | Mediates metabolic effects of acadesine |
| LATS1 | Tumor suppressor kinase | Activated by acadesine independently of AMPK |
| LATS2 | Tumor suppressor kinase | Activated by acadesine independently of AMPK |
| BCL2 | Anti-apoptotic protein | Bcl-2-high cells are sensitized to acadesine |
| PIK3CA | PI3K catalytic subunit | PI3K/Akt pathway mediates acadesine effects on tissue factor |
| AKT1 | Serine/threonine kinase | Activated by acadesine in endothelial cells |
| CD20 | B-lymphocyte antigen | Target of rituximab, synergizes with acadesine |
| TF | Tissue factor | Inhibited by acadesine via PI3K/Akt |
| CASP3 | Apoptosis executioner | Mediates acadesine-induced apoptosis |
| CASP9 | Apoptosis initiator | Mediates acadesine-induced apoptosis |
| BAX | Pro-apoptotic protein | Involved in acadesine-induced apoptosis |
| BCL2L1 | Bcl-xL anti-apoptotic | Modulates sensitivity to acadesine |
| MCL1 | Anti-apoptotic protein | Modulates sensitivity to acadesine |
| DNMT3A | DNA methyltransferase | Associated with azacitidine resistance circumvented by acadesine |
| TET2 | DNA demethylase | Associated with azacitidine resistance circumvented by acadesine |
| TP53 | Tumor suppressor | May influence response to acadesine |
How Is cellular response to acadesine Regulated?
The cellular response to acadesine is regulated at multiple levels. AMPK activation by ZMP is a primary regulatory node, but AMPK-independent pathways such as LATS1/2 activation also play a role. The PI3K/Akt pathway modulates acadesine effects on tissue factor and thrombus formation. Additionally, Bcl-2 family proteins regulate apoptotic sensitivity to acadesine. In hematological malignancies, resistance mechanisms involving DNA methylation and TP53 status may affect the response to acadesine.
cellular response to acadesine and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| BCL2 | Mantle cell lymphoma | Bcl-2-high lymphoma cell lines with CRISPR knockout of BCL2 |
| LATS1/2 | Cancer proliferation | LATS1/2 knockout cell lines treated with acadesine |
| PIK3CA/AKT1 | Thrombosis and inflammation | Endothelial cells with PI3K/Akt pathway mutations |
| DNMT3A/TET2 | Myelodysplastic syndrome | Azacitidine-resistant leukemia cell lines with CRISPR knock-in of mutations |
| TP53 | Acute myeloid leukemia | TP53 knockout or mutant knock-in AML models |
Mantle cell lymphoma
Acadesine shows anti-tumor activity in mantle cell lymphoma, particularly in Bcl-2-high cells, and synergizes with ABT-199 and rituximab [1, 3]. The cellular response involves apoptosis and cell cycle arrest, making acadesine a potential therapeutic agent for this aggressive lymphoma.
Myelodysplastic syndrome and acute myeloid leukemia
Acadesine circumvents azacitidine resistance in myelodysplastic syndrome and acute myeloid leukemia, offering a strategy for patients who fail hypomethylating agents. The response involves AMPK activation and possibly other pathways that overcome resistance.
Cardiovascular inflammation and thrombosis
Acadesine inhibits tissue factor induction and thrombus formation via PI3K/Akt, suggesting a role in preventing cardiovascular inflammation and thrombosis [2, 4]. Adenosinergic drugs like acadesine are explored for cardiovascular disorders.
From cellular response to acadesine-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does AMPK mediate acadesine-induced apoptosis? | PRKAA1/2 double knockout cell lines |
| Is LATS1/2 activation required for acadesine antiproliferative effects? | LATS1/2 knockout cells with acadesine treatment |
| How does Bcl-2 expression affect acadesine sensitivity? | BCL2 overexpression or knockout lymphoma cells |
| Can acadesine overcome azacitidine resistance? | Azacitidine-resistant MDS/AML cells with DNMT3A/TET2 mutations |
| What is the role of PI3K/Akt in acadesine-induced tissue factor inhibition? | PIK3CA mutant or AKT1 knockout endothelial cells |
| Does TP53 status influence acadesine response? | TP53 knockout or mutant knock-in cancer cell lines |
How to Study the cellular response to acadesine Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify acadesine-responsive genes and pathways |
| Phosphoproteomics | Kinase activity and signaling | Map AMPK and PI3K/Akt phosphorylation events |
| Flow cytometry | Apoptosis and cell cycle | Quantify acadesine-induced cell death |
| Seahorse assay | Glycolysis and oxidative phosphorylation | Measure metabolic reprogramming |
| Western blot | Protein expression and phosphorylation | Validate specific pathway activation |
| CRISPR screening | Gene essentiality and resistance | Identify genes required for acadesine response |
| Immunofluorescence | Protein localization and activation | Visualize LATS1/2 or AMPK translocation |
Transcriptomic profiling
RNA-seq can reveal global gene expression changes induced by acadesine, identifying pathways and targets of the cellular response [1, 7]. This method helps uncover AMPK-dependent and independent transcriptional programs.
Phosphoproteomics
Phosphoproteomics measures changes in kinase activity and signaling cascades upon acadesine treatment, such as AMPK and PI3K/Akt phosphorylation events [2, 7]. It provides a system-wide view of the response.
Apoptosis assays
Flow cytometry with Annexin V/PI staining and caspase activity assays quantify acadesine-induced apoptosis in cancer cells [1, 3]. These methods are essential for evaluating therapeutic potential.
Metabolic flux analysis
Seahorse extracellular flux analysis and metabolomics measure changes in glycolysis and oxidative phosphorylation following acadesine treatment. This reveals the metabolic reprogramming central to GO:1904102.
How CRISPR Can Be Used to Study GO:1904102 cellular response to acadesine
Knockout
CRISPR knockout of candidate genes such as PRKAA1, LATS1, or BCL2 can determine their necessity in the cellular response to acadesine [1, 7]. For example, PRKAA1/2 double knockout cells can test AMPK dependence.
Point Mutation
Introducing point mutations in genes like TP53 or PIK3CA can model clinical variants and assess their impact on acadesine sensitivity. This helps link specific mutations to drug response.
Knock-in
Knock-in of tagged proteins (e.g., GFP-LATS1) allows real-time imaging of acadesine-induced translocation and activation. This provides spatial and temporal insights.
Overexpression
Overexpression of BCL2 or MCL1 can test whether these anti-apoptotic proteins confer resistance to acadesine. This models Bcl-2-high lymphomas.
How EDITGENE Supports cellular response to acadesine Research
Researchers studying cellular response to acadesine-related genes often need to determine whether a candidate gene is causally involved in the response or merely a bystander. CRISPR-based models provide the gold standard for establishing causality, and EDITGENE offers a comprehensive suite of services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for cellular response to acadesine research.
Frequently Asked Questions About cellular response to acadesine
What is GO:1904102?
GO:1904102 is the Gene Ontology term for cellular response to acadesine, defined as any process that results in a change in state or activity of a cell as a result of an acadesine stimulus.
What is acadesine?
Acadesine (AICAR) is an adenosine analog that activates AMPK and is used experimentally to study metabolic stress and apoptosis [1, 2, 7].
What genes are involved in cellular response to acadesine?
Key genes include PRKAA1/2 (AMPK), LATS1/2, BCL2, PIK3CA, AKT1, and TP53 [1, 2, 7, 8].
How does acadesine induce apoptosis?
Acadesine induces apoptosis through AMPK activation and AMPK-independent pathways, involving Bcl-2 family proteins and caspases [1, 7].
What diseases are associated with acadesine response?
Acadesine response is linked to mantle cell lymphoma, myelodysplastic syndrome, acute myeloid leukemia, and cardiovascular thrombosis [1, 2, 3, 8].
Can acadesine overcome drug resistance?
Yes, acadesine circumvents azacitidine resistance in MDS and AML.
What is the role of AMPK in acadesine response?
AMPK mediates many metabolic effects of acadesine, but some effects are AMPK-independent, such as LATS1/2 activation.
How can I study cellular response to acadesine?
Use CRISPR knockout, knock-in, overexpression models, RNA-seq, phosphoproteomics, and apoptosis assays [1, 2, 7].
Does acadesine affect thrombosis?
Acadesine inhibits tissue factor induction and thrombus formation via PI3K/Akt.
What cell models are available for acadesine research?
EDITGENE provides custom knockout, point mutation, knock-in, and overexpression cell models for acadesine response studies.
Conclusion
GO:1904102 cellular response to acadesine encompasses a complex network of signaling events, including AMPK-dependent and independent pathways, apoptosis, and metabolic reprogramming. Its relevance spans cancer, cardiovascular disease, and drug resistance. Leveraging CRISPR models and multi-omics approaches will continue to unravel the mechanisms and therapeutic potential of acadesine. EDITGENE offers the tools and expertise to accelerate this research.
References
- 1. Montraveta A et al.. 2015. Bcl-2high mantle cell lymphoma cells are sensitized to acadesine with ABT-199.. Oncotarget 6(25):21159-72 PMID: 26110568
- 2. Zhang W et al.. 2010. Acadesine inhibits tissue factor induction and thrombus formation by activating the phosphoinositide 3-kinase/Akt signaling pathway.. Arterioscler Thromb Vasc Biol 30(5):1000-6 PMID: 20185792
- 3. Montraveta A et al.. 2014. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma.. Oncotarget 5(3):726-39 PMID: 24519895
- 4. Hill GE. 1998. Cardiopulmonary bypass-induced inflammation: is it important?. J Cardiothorac Vasc Anesth 12(2 Suppl 1):21-5 PMID: 9583572
- 5. Szentmiklósi AJ et al.. 2011. Novel trends in the treatment of cardiovascular disorders: site- and event- selective adenosinergic drugs.. Curr Med Chem 18(8):1164-87 PMID: 21291368
- 7. Philippe C et al.. 2018. AICAR Antiproliferative Properties Involve the AMPK-Independent Activation of the Tumor Suppressors LATS 1 and 2.. Neoplasia 20(6):555-562 PMID: 29730476
- 8. Cluzeau T et al.. 2019. Acadesine Circumvents Azacitidine Resistance in Myelodysplastic Syndrome and Acute Myeloid Leukemia.. Int J Mol Sci 21(1) PMID: 31881723
