IRF-1 expression is induced by cisplatin in ovarian cancer cells and limits drug effectiveness

Pavan, Simona; Olivero, Martina; Corà, Davide

doi:10.1016/j.ejca.2012.09.024

Cited by 26 publications

(23 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Resistance to platinum agents, such as Cisplatin, remains a significant source of morbidity [43; 61] and overcoming resistance is a key goal in ovarian cancer treatment [62; 63; 64; 65]. The discovery of new targets mediating resistance and overcoming or reversing resistance to chemotherapy has begun to emerge [35; 44; 66; 67; 68]. Recent gene expression studies have linked not only the BMP pathway but also the Epithelial to Mesenchymal Transition (EMT) process to chemoresistance [43; 61; 69; 70].…”

Section: Discussionmentioning

confidence: 99%

Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

et al. 2015

View full text Add to dashboard Cite

The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Mechanistically, cisplatin induces IRF1-dependent and p53-independent p21 expression and cell cycle arrest. Because cisplatin is more effective in proliferating cancer cells, the induction of cell cycle arrest may counteract with the anticancer activity of cisplatin [53]. However, this study does not defy the tumor-suppressive role of IRF1 because IRF1 overexpression still inhibits the transformed phenotypes of ovarian cancer cells [53].…”

Section: Discussionmentioning

confidence: 82%

“…Therefore, pre-therapeutic IRF1 expression can be used as a novel predictive biomarker for chemotherapy responses, and pre-stimulation of IRF1 by cytokine therapy can enhance the efficacy of chemotherapeutic agents. It is controversial that IRF1 expression is upregulated by cisplatin, but limits drug effectiveness in ovarian cancer cells [53]. Mechanistically, cisplatin induces IRF1-dependent and p53-independent p21 expression and cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

Sequential Interferon β-Cisplatin Treatment Enhances the Surface Exposure of Calreticulin in Cancer Cells via an Interferon Regulatory Factor 1-Dependent Manner

Yang

Hsieh

et al. 2020

Biomolecules

View full text Add to dashboard Cite

Immunogenic cell death (ICD) refers to a unique form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Accumulating evidence indicates that the efficacy of conventional anticancer agents relies on not only their direct cytostatic/cytotoxic effects but also the activation of antitumor ICD. Common anticancer ICD inducers include certain chemotherapeutic agents (such as anthracyclines, oxaliplatin, and bortezomib), radiotherapy, photodynamic therapy (PDT), and oncolytic virotherapies. However, most chemotherapeutic reagents are inefficient or fail to trigger ICD. Therefore, better understanding on the molecular determinants of chemotherapy-induced ICD will help in the development of more efficient combinational anticancer strategies through converting non-or relatively weak ICD inducers into bona fide ICD inducers. In this study, we found that sequential, but not concurrent, treatment of cancer cells with interferon β (IFNβ), a type I IFN, and cisplatin (an inefficient ICD inducer) can enhance the expression of ICD biomarkers in cancer cells, including surface translocation of an endoplasmic reticulum (ER) chaperone, calreticulin (CRT), and phosphorylation of the eukaryotic translation initiation factor alpha (eIF2α). These results suggest that exogenous IFNβ may activate molecular determinants that convert cisplatin into an ICD inducer. Further bioinformatics and in vitro experimental analyses found that interferon regulatory factor 1 (IRF1) acted as an essential mediator of surface CRT exposure by sequential IFNβ-cisplatin combination. Our findings not only help to design more effective combinational anticancer therapy using IFNβ and cisplatin, but also provide a novel insight into the role of IRF1 in connecting the type I IFN responses and ICD.

show abstract

“…An enrichment analysis of Hallmark (12) and Reactome (13) gene sets revealed that resistance was associated with a global repression of proliferation and translation and the activation of genes involved with interferon signaling, KRAS signaling and epithelial-to-mesenchymal transition (EMT) ( Figure S3). All of these are processes previously reported to be involved in chemo-resistance or response to genotoxic injury (14)(15)(16). An unsupervised analysis revealed that, while the S clones had similar transcriptional profiles, the profiles of the R clones were highly heterogeneous ( Figure 2B).…”

Section: Phenotypic and Molecular Characterization Of Isogenic Resistmentioning

confidence: 76%

“…Activation of interferon signaling is triggered by the DNA damage response (DDR) (25) and was previously observed in response to genotoxic stress. Expression of IRF1, a main effector of interferon signaling, is induced by cisplatin and may limit this drug's effectiveness (15). Importantly, it is not yet clear whether the DDR-mediated response can be targeted to prevent or reverse resistance.…”

Section: Discussionmentioning

confidence: 99%

Single-cell characterization of step-wise acquisition of carboplatin resistance in ovarian cancer

Wenzel

Champa²,

Venkatesh

et al. 2017

Preprint

View full text Add to dashboard Cite

Acquired resistance to carboplatin is a major obstacle to the cure of ovarian cancer, but its molecular underpinnings are still poorly defined. We selected multiple clones derived from a single cell in parallel for similar levels of resistance to carboplatin. The resistant clones showed no significant genetic alterations, but each one activated different mechanisms of resistance resulting in transcriptional heterogeneity. Single-cell mRNA sequencing defined multiple transcriptional states associated with clone identity and resistance evolution, and identified a subset of unselected parental cells that were already in a resistant state. Six expression signatures derived from the resistant states distinguished primary from recurrent high-grade serous ovarian cancers, predicted both response and survival and disclosed functional differences between intrinsic and acquired resistance. This multidimensional, single-cell analysis offers new insights into the dynamics of the acquisition of resistance to carboplatin, a drug of major importance to the treatment of ovarian and other cancers.

show abstract

IRF-1 expression is induced by cisplatin in ovarian cancer cells and limits drug effectiveness

Cited by 26 publications

References 29 publications

Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

Sequential Interferon β-Cisplatin Treatment Enhances the Surface Exposure of Calreticulin in Cancer Cells via an Interferon Regulatory Factor 1-Dependent Manner

Single-cell characterization of step-wise acquisition of carboplatin resistance in ovarian cancer

Contact Info

Product

Resources

About