Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia
Abstract Background Development of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute myeloid leukemia (AML) patients needs to be greatly improved, as relapse and refractory disease are still diffic...
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-023-02944-4 |
| _version_ | 1797822643833929728 |
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| author | Laia Cuesta-Casanovas Jennifer Delgado-Martínez Josep M. Cornet-Masana José M. Carbó Antònia Banús-Mulet Francesca Guijarro Jordi Esteve Ruth M. Risueño |
| author_facet | Laia Cuesta-Casanovas Jennifer Delgado-Martínez Josep M. Cornet-Masana José M. Carbó Antònia Banús-Mulet Francesca Guijarro Jordi Esteve Ruth M. Risueño |
| author_sort | Laia Cuesta-Casanovas |
| collection | DOAJ |
| description | Abstract Background Development of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute myeloid leukemia (AML) patients needs to be greatly improved, as relapse and refractory disease are still difficult to manage. Thus, new therapeutic approaches are needed. Based on in silico-generated preliminary data and the literature, the role of the prolactin (PRL)-mediated signaling was interrogated in AML. Methods Protein expression and cell viability were determined by flow cytometry. Repopulation capacity was studied in murine xenotransplantation assays. Gene expression was measured by qPCR and luciferase-reporters. SA-β-Gal staining was used as a senescence marker. Results The prolactin receptor (PRLR) was upregulated in AML cells, as compared to their healthy counterpart. The genetic and molecular inhibition of this receptor reduced the colony-forming potential. Disruption of the PRLR signaling, either using a mutant PRL or a dominant-negative isoform of PRLR, reduced the leukemia burden in vivo, in xenotransplantation assays. The expression levels of PRLR directly correlated with resistance to cytarabine. Indeed, acquired cytarabine resistance was accompanied with the induction of PRLR surface expression. The signaling associated to PRLR in AML was mainly mediated by Stat5, in contrast to the residual function of Stat3. In concordance, Stat5 mRNA was significantly overexpressed at mRNA levels in relapse AML samples. A senescence-like phenotype, measured by SA-β-gal staining, was induced upon enforced expression of PRLR in AML cells, partially dependent on ATR. Similar to the previously described chemoresistance-induced senescence in AML, no cell cycle arrest was observed. Additionally, the therapeutic potential of PRLR in AML was genetically validated. Conclusions These results support the role of PRLR as a therapeutic target for AML and the further development of drug discovery programs searching for specific PRLR inhibitors. |
| first_indexed | 2024-03-13T10:11:07Z |
| format | Article |
| id | doaj.art-00026095bd1140f2bb033ebf31627389 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-03-13T10:11:07Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-00026095bd1140f2bb033ebf316273892023-05-21T11:28:00ZengBMCCancer Cell International1475-28672023-05-0123111810.1186/s12935-023-02944-4Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemiaLaia Cuesta-Casanovas0Jennifer Delgado-Martínez1Josep M. Cornet-Masana2José M. Carbó3Antònia Banús-Mulet4Francesca Guijarro5Jordi Esteve6Ruth M. Risueño7Josep Carreras Leukaemia Research Institute (IJC)Josep Carreras Leukaemia Research Institute (IJC)Josep Carreras Leukaemia Research Institute (IJC)Josep Carreras Leukaemia Research Institute (IJC)Josep Carreras Leukaemia Research Institute (IJC)Josep Carreras Leukaemia Research Institute (IJC)Josep Carreras Leukaemia Research Institute (IJC)Josep Carreras Leukaemia Research Institute (IJC)Abstract Background Development of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute myeloid leukemia (AML) patients needs to be greatly improved, as relapse and refractory disease are still difficult to manage. Thus, new therapeutic approaches are needed. Based on in silico-generated preliminary data and the literature, the role of the prolactin (PRL)-mediated signaling was interrogated in AML. Methods Protein expression and cell viability were determined by flow cytometry. Repopulation capacity was studied in murine xenotransplantation assays. Gene expression was measured by qPCR and luciferase-reporters. SA-β-Gal staining was used as a senescence marker. Results The prolactin receptor (PRLR) was upregulated in AML cells, as compared to their healthy counterpart. The genetic and molecular inhibition of this receptor reduced the colony-forming potential. Disruption of the PRLR signaling, either using a mutant PRL or a dominant-negative isoform of PRLR, reduced the leukemia burden in vivo, in xenotransplantation assays. The expression levels of PRLR directly correlated with resistance to cytarabine. Indeed, acquired cytarabine resistance was accompanied with the induction of PRLR surface expression. The signaling associated to PRLR in AML was mainly mediated by Stat5, in contrast to the residual function of Stat3. In concordance, Stat5 mRNA was significantly overexpressed at mRNA levels in relapse AML samples. A senescence-like phenotype, measured by SA-β-gal staining, was induced upon enforced expression of PRLR in AML cells, partially dependent on ATR. Similar to the previously described chemoresistance-induced senescence in AML, no cell cycle arrest was observed. Additionally, the therapeutic potential of PRLR in AML was genetically validated. Conclusions These results support the role of PRLR as a therapeutic target for AML and the further development of drug discovery programs searching for specific PRLR inhibitors.https://doi.org/10.1186/s12935-023-02944-4Prolactin receptorLeukemiaSenescenceBiomarkerDifferentiation |
| spellingShingle | Laia Cuesta-Casanovas Jennifer Delgado-Martínez Josep M. Cornet-Masana José M. Carbó Antònia Banús-Mulet Francesca Guijarro Jordi Esteve Ruth M. Risueño Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia Cancer Cell International Prolactin receptor Leukemia Senescence Biomarker Differentiation |
| title | Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia |
| title_full | Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia |
| title_fullStr | Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia |
| title_full_unstemmed | Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia |
| title_short | Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia |
| title_sort | prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia |
| topic | Prolactin receptor Leukemia Senescence Biomarker Differentiation |
| url | https://doi.org/10.1186/s12935-023-02944-4 |
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