GO:0072718 response to cisplatin: DNA Damage Response Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0072718 response to cisplatin describes any cellular or organismal change triggered by cisplatin, a platinum-based chemotherapeutic that forms DNA adducts and activates the DNA damage response.
• Cisplatin response involves p53 activation, eEF2 kinase signaling, and transcriptional reprogramming that determines cell survival or death.
• Key genes include TP53, HIF1A, NPEPPS, COX17, and STING pathway components, each contributing to drug sensitivity or resistance.
• Genetic variability in HIF1A and expression of NPEPPS are linked to clinical cisplatin resistance in mesothelioma and other cancers.
• Cisplatin response can be potentiated by targeting molecular pathways such as STING signaling, offering therapeutic opportunities.
• CRISPR knockout, point mutation, knock-in, and overexpression models enable causal dissection of genes involved in cisplatin response.
Description
GO:0072718 response to cisplatin is a biological process defined as any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a cisplatin stimulus. Cisplatin is a widely used platinum-based anticancer drug that exerts its cytotoxic effects primarily by forming covalent adducts with DNA, leading to replication stress and activation of the DNA damage response. Understanding how cells respond to cisplatin is critical for predicting drug efficacy, overcoming resistance, and identifying biomarkers of sensitivity. The response encompasses a complex network of signaling pathways, transcriptional programs, and post-translational modifications that collectively determine whether a cell survives, repairs damage, or undergoes apoptosis. Research into this process has revealed key roles for p53 activation, eEF2 kinase, and metabolic regulators such as NPEPPS and COX17. Moreover, genetic variability in genes like HIF1A can influence clinical outcomes in patients treated with cisplatin-based regimens. This article synthesizes current knowledge on the mechanisms, genes, and experimental models used to study GO:0072718, providing a resource for researchers in cancer biology and pharmacology.
response to cisplatin At A Glance
| GO ID | GO:0072718 |
|---|---|
| GO term | response to cisplatin |
| Ontology | biological_process |
| Synonym | none |
| Major function | Cellular and organismal response to cisplatin-induced DNA damage and stress |
| Related processes | DNA damage response, apoptosis, p53 signaling, drug resistance |
| Key regulators | TP53, eEF2K, HIF1A, NPEPPS, COX17, STING1 |
| Disease relevance | Cancer chemotherapy response, platinum resistance, ototoxicity |
What Is GO:0072718?
In our own words, GO:0072718 response to cisplatin refers to the collection of molecular, cellular, and physiological changes that occur when a cell or organism encounters cisplatin. This includes alterations in gene expression, enzyme activity, signal transduction, and cellular behaviors such as apoptosis, cell cycle arrest, or DNA repair. The term captures the entirety of the biological reaction to cisplatin, from initial sensing of DNA damage to downstream effector responses.
Why Is response to cisplatin Important in Cell Biology?
Understanding GO:0072718 is essential because cisplatin remains a first-line chemotherapeutic for many solid tumors, yet resistance and toxicity limit its efficacy. The cellular response to cisplatin determines whether tumor cells survive or die, directly impacting patient outcomes. Elucidating the molecular players in this response can reveal biomarkers for patient stratification and targets for combination therapies to potentiate cisplatin sensitivity.
• Cisplatin is a cornerstone of treatment for testicular, ovarian, lung, bladder, and head and neck cancers.
• The DNA damage response triggered by cisplatin is a major determinant of drug sensitivity.
• p53 activation is central to cisplatin-induced apoptosis, and its dysfunction promotes resistance.
• eEF2 kinase coordinates the DNA damage response to cisplatin by supporting p53 activation.
• NPEPPS has been identified as a druggable driver of platinum resistance.
• HIF1A genetic variability affects response to cisplatin-based therapy in malignant mesothelioma.
• COX17-mediated cisplatin transport contributes to cochlear damage and ototoxicity.
• STING signaling activation can potentiate cisplatin sensitivity in triple-negative breast cancer.
• Global gene expression changes in response to cisplatin have been characterized in model organisms.
• Molecular approaches to potentiate cisplatin responsiveness are actively being developed.
What Happens During response to cisplatin?
Cisplatin Uptake and DNA Adduct Formation
In simple terms: Cisplatin enters cells and binds to DNA, causing damage that triggers a stress response.
Cisplatin is taken up by cells through transporters such as COX17, and once inside, it forms covalent adducts with DNA, primarily intrastrand crosslinks. These lesions distort the DNA helix and are recognized by cellular surveillance machinery, initiating the DNA damage response. The extent of adduct formation correlates with cytotoxicity and is influenced by cellular uptake and detoxification pathways.
Activation of the DNA Damage Response and p53
In simple terms: The cell senses DNA damage and activates p53, which decides whether to repair or die.
Cisplatin-induced DNA damage activates ATM/ATR kinases, which phosphorylate and stabilize p53. eEF2 kinase coordinates this response by supporting p53 activation, and its inhibition impairs p53-mediated apoptosis. p53 then transcriptionally activates target genes involved in cell cycle arrest, DNA repair, and apoptosis, determining cell fate.
Transcriptional Reprogramming
In simple terms: The cell changes which genes are turned on or off to cope with cisplatin stress.
Global gene expression profiling in fission yeast and mammalian cells has revealed widespread transcriptional changes in response to cisplatin, including induction of stress response genes, DNA repair genes, and metabolic regulators. These changes are mediated by transcription factors such as p53 and HIF1A, and can influence survival.
Metabolic and Signaling Adaptations
In simple terms: Cells adjust their metabolism and signaling to resist or succumb to cisplatin.
NPEPPS, a puromycin-sensitive aminopeptidase, drives platinum resistance by modulating protein turnover and metabolic pathways. COX17, a copper chaperone, binds cisplatin and mediates its transport to the cochlea, contributing to ototoxicity through mitochondrial dysfunction and pyroptosis. STING signaling activation can enhance cisplatin sensitivity by promoting immune responses.
Cell Fate Decision: Survival, Apoptosis, or Senescence
In simple terms: Depending on the signals, the cell may repair damage, die, or enter permanent growth arrest.
The integration of DNA damage, p53 activation, and metabolic cues determines whether a cell undergoes apoptosis, senescence, or survives with repaired DNA. Resistance mechanisms often involve defective apoptosis, enhanced DNA repair, or altered drug transport. Understanding these decision points is key to overcoming cisplatin resistance.
Key Genes Involved in GO:0072718 response to cisplatin
The following genes and proteins are central to the cellular response to cisplatin, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TP53 | Tumor suppressor; activates apoptosis and cell cycle arrest upon DNA damage | Mutations in TP53 are associated with cisplatin resistance |
| EEF2K | eEF2 kinase; coordinates DNA damage response and supports p53 activation | Target for enhancing cisplatin sensitivity |
| HIF1A | Hypoxia-inducible factor 1-alpha; regulates oxygen homeostasis and drug response | Genetic variability affects cisplatin treatment outcome in mesothelioma |
| NPEPPS | Puromycin-sensitive aminopeptidase; drives platinum resistance | Druggable target to overcome resistance |
| COX17 | Copper chaperone; transports cisplatin and mediates ototoxicity | Potential target to reduce hearing loss |
| STING1 | Stimulator of interferon genes; activates immune signaling | Activation potentiates cisplatin sensitivity in breast cancer |
| ATM | Ataxia telangiectasia mutated; kinase that senses DNA double-strand breaks | Central to DNA damage response |
| ATR | Ataxia telangiectasia and Rad3-related; kinase that responds to replication stress | Mediates cisplatin-induced damage signaling |
| CDKN1A | p21; cyclin-dependent kinase inhibitor; mediates cell cycle arrest | Downstream effector of p53 |
| BAX | Pro-apoptotic Bcl-2 family member | Effector of p53-mediated apoptosis |
| BCL2 | Anti-apoptotic protein | Overexpression promotes cisplatin resistance |
| ERCC1 | Excision repair cross-complementing 1; nucleotide excision repair | Predictive marker for platinum response |
| XPF | Xeroderma pigmentosum group F; DNA repair endonuclease | Involved in repair of cisplatin adducts |
| MRP2 | Multidrug resistance-associated protein 2; drug efflux pump | Mediates cisplatin efflux and resistance |
| ATP7A | Copper-transporting ATPase; mediates cisplatin efflux | Alters intracellular drug accumulation |
| ATP7B | Copper-transporting ATPase; mediates cisplatin efflux | Alters intracellular drug accumulation |
| SLC31A1 | Copper transporter 1; mediates cisplatin uptake | Determines drug sensitivity |
How Is response to cisplatin Regulated?
The response to cisplatin is regulated at multiple levels. The DNA damage response kinases ATM and ATR initiate signaling cascades that activate p53 and other effectors. eEF2 kinase modulates translation and supports p53 activation, linking protein synthesis to the damage response. HIF1A transcriptional activity is regulated by oxygen availability and genetic polymorphisms, influencing drug response. NPEPPS activity affects protein turnover and metabolic adaptation, contributing to resistance. Additionally, STING signaling can be activated by cisplatin-induced DNA damage, leading to interferon production and immune modulation. These regulatory layers provide multiple nodes for therapeutic intervention.
response to cisplatin and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TP53 | Cisplatin resistance in multiple cancers | TP53 knockout or point-mutant cell lines |
| NPEPPS | Platinum resistance in bladder and other cancers | NPEPPS knockout or overexpression models |
| HIF1A | Malignant mesothelioma response to cisplatin | HIF1A knock-in of variant alleles |
| COX17 | Cisplatin-induced ototoxicity | Cox17 knockout mice or cochlear cell lines |
| STING1 | Triple-negative breast cancer sensitivity | STING1 overexpression or knockout in TNBC cells |
Cisplatin Resistance in Cancer
Resistance to cisplatin is a major clinical challenge in cancers such as ovarian, lung, and head and neck carcinomas. Mechanisms include reduced drug uptake, increased efflux, enhanced DNA repair, and defective apoptosis. NPEPPS has been identified as a druggable driver of platinum resistance, and its inhibition restores sensitivity in preclinical models. Genetic variability in HIF1A is associated with differential response to cisplatin-based therapy in malignant mesothelioma. Targeting these pathways may improve patient outcomes.
Cisplatin-Induced Ototoxicity
Cisplatin causes hearing loss in a significant proportion of patients, limiting its use. COX17 transports cisplatin into cochlear cells, where it binds Myosin IIA and triggers mitochondrial dysfunction and pyroptosis. This mechanism provides potential targets for preventing ototoxicity without compromising antitumor efficacy.
Enhancing Cisplatin Sensitivity
Molecular approaches to potentiate cisplatin responsiveness are being explored, including activation of STING signaling. In triple-negative breast cancer, Astragaloside IV potentiates cisplatin sensitivity via STING pathway activation. Combining cisplatin with immune modulators or targeted agents may overcome resistance and improve outcomes.
From response to cisplatin-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of TP53 affect cisplatin-induced apoptosis? | TP53 knockout cancer cell lines |
| Does eEF2K inhibition potentiate cisplatin sensitivity? | EEF2K knockout or point-mutant cells |
| Does NPEPPS drive platinum resistance? | NPEPPS overexpression and knockout models |
| Do HIF1A variants alter cisplatin response? | HIF1A knock-in of specific SNPs |
| Does COX17 mediate cisplatin ototoxicity? | Cox17 knockout mice |
| Can STING activation enhance cisplatin sensitivity? | STING1 overexpression in TNBC cells |
How to Study the response to cisplatin Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify transcriptional response to cisplatin |
| Proteomics | Protein abundance and modifications | Detect signaling changes and drug targets |
| CRISPR knockout screen | Gene essentiality and drug sensitivity | Discover resistance drivers like NPEPPS |
| Phosphoproteomics | Kinase activity and signaling networks | Map DNA damage response pathways |
| Immunofluorescence | DNA damage foci and apoptosis | Visualize cellular response |
| Mitochondrial function assays | Mitochondrial membrane potential and ROS | Assess ototoxicity mechanisms |
| STING reporter assays | Interferon pathway activation | Evaluate immune modulation |
Transcriptomic Profiling
RNA-seq and microarray analysis have been used to characterize global gene expression changes in response to cisplatin, revealing transcriptional programs that mediate survival and resistance. These methods identify differentially expressed genes and pathways that can be targeted therapeutically.
Proteomic and Phosphoproteomic Analysis
Mass spectrometry-based proteomics can quantify changes in protein abundance and post-translational modifications after cisplatin treatment, uncovering signaling events such as p53 phosphorylation and eEF2 kinase activation. These approaches provide a systems-level view of the response.
Functional Genomics with CRISPR Screens
CRISPR knockout and activation screens enable unbiased identification of genes that modulate cisplatin sensitivity or resistance. Such screens have highlighted NPEPPS as a driver of platinum resistance, demonstrating the power of functional genomics in this field.
Imaging and Cell-Based Assays
Fluorescence microscopy and live-cell imaging can visualize DNA damage foci, apoptosis, and mitochondrial dysfunction in response to cisplatin. These assays provide spatial and temporal resolution of the cellular response.
How CRISPR Can Be Used to Study GO:0072718 response to cisplatin
Knockout
CRISPR knockout of genes such as TP53, EEF2K, or NPEPPS allows researchers to determine their causal role in cisplatin response. For example, EEF2K knockout impairs p53 activation and reduces cisplatin-induced apoptosis. NPEPPS knockout sensitizes resistant cells to platinum.
Point Mutation
Introducing specific point mutations, such as those in TP53 or HIF1A, can model clinically relevant variants and assess their impact on cisplatin sensitivity. This approach helps link genotype to drug response.
Knock-in
Knock-in of tagged or reporter genes, such as STING1 or COX17, enables tracking of protein localization and function in response to cisplatin. This can reveal dynamic changes in protein expression and interactions.
Overexpression
Overexpression of resistance genes like NPEPPS or anti-apoptotic BCL2 can confer cisplatin resistance, providing models to test reversal strategies. Conversely, overexpression of STING1 can enhance sensitivity.
How EDITGENE Supports response to cisplatin Research
Researchers studying response to cisplatin-related genes often need to determine whether a candidate gene is causally involved in drug sensitivity, resistance, or toxicity. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models, enabling rigorous functional validation of genes implicated in GO:0072718.
Contact EDITGENE today to design your custom CRISPR model for response to cisplatin research.
Frequently Asked Questions About response to cisplatin
What is GO:0072718 response to cisplatin?
GO:0072718 is a Gene Ontology biological process term that describes any change in a cell or organism resulting from exposure to cisplatin, including DNA damage response, gene expression changes, and cell fate decisions.
What genes are involved in response to cisplatin?
Key genes include TP53, EEF2K, HIF1A, NPEPPS, COX17, and STING1, among others, which regulate DNA repair, apoptosis, drug transport, and immune signaling.
How does cisplatin cause DNA damage?
Cisplatin forms covalent adducts with DNA, primarily intrastrand crosslinks, which distort the helix and activate the DNA damage response.
What is the role of p53 in cisplatin response?
p53 is activated upon cisplatin-induced DNA damage and transcriptionally regulates genes that cause cell cycle arrest, DNA repair, or apoptosis.
How does eEF2 kinase affect cisplatin sensitivity?
eEF2 kinase coordinates the DNA damage response by supporting p53 activation; its inhibition impairs p53-mediated apoptosis and can alter sensitivity.
What is NPEPPS and how does it relate to platinum resistance?
NPEPPS is a puromycin-sensitive aminopeptidase that drives platinum resistance; its inhibition restores sensitivity to cisplatin in resistant cells.
Can HIF1A variants affect cisplatin treatment outcome?
Yes, genetic variability in HIF1A has been associated with differential response to cisplatin-based therapy in malignant mesothelioma.
How does COX17 contribute to cisplatin ototoxicity?
COX17 transports cisplatin into cochlear cells, where it binds Myosin IIA and triggers mitochondrial dysfunction and pyroptosis, leading to hearing loss.
Does STING signaling influence cisplatin sensitivity?
Activation of STING signaling can potentiate cisplatin sensitivity in triple-negative breast cancer, suggesting a role for immune modulation.
What experimental models are used to study response to cisplatin?
Common models include CRISPR knockout, point mutation, knock-in, and overexpression cell lines, as well as transcriptomic and proteomic profiling.
Conclusion
GO:0072718 response to cisplatin encompasses a complex network of molecular and cellular events that determine the efficacy and toxicity of this widely used chemotherapeutic. Key genes such as TP53, EEF2K, NPEPPS, HIF1A, COX17, and STING1 play critical roles in drug sensitivity, resistance, and adverse effects. Understanding these mechanisms is essential for developing biomarkers and combination therapies to improve patient outcomes. CRISPR-based models and functional genomics provide powerful tools to dissect this process and identify new therapeutic targets.
References
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- 2. Setina M et al.. 2025. Genetic variability of HIF1A and response to treatment with cisplatin in combination with pemetrexed or gemcitabine in patients with malignant mesothelioma.. Radiol Oncol 59(3):403-411 PMID: 40959922
- 4. Jones RT et al.. 2024. NPEPPS Is a Druggable Driver of Platinum Resistance.. Cancer Res 84(10):1699-1718 PMID: 38535994
- 5. Gatti L et al.. 2004. Global gene expression of fission yeast in response to cisplatin.. Cell Mol Life Sci 61(17):2253-63 PMID: 15338055
- 6. Peng J et al.. 2025. Cisplatin transported by COX17 induces cochlear damage by binding Myosin IIA to regulate cell pyroptosis induced by mitochondrial dysfunction.. Life Sci 380:123961 PMID: 40945651
- 7. Jain A et al.. 2017. Molecular approaches to potentiate cisplatin responsiveness in carcinoma therapeutics.. Expert Rev Anticancer Ther 17(9):815-825 PMID: 28705091
- 8. Bai B et al.. 2025. Astragaloside IV potentiates cisplatin sensitivity in triple-negative breast cancer via STING signaling pathway activation.. Phytomedicine 148:157330 PMID: 41016300
