Abstract 2892: Genetic inhibition of STAT3 increases medulloblastoma chemosensitivity
| Autor: | Sutapa Ray, Donald Coulter, Phillip Wilder, Jason Sughroue, Nagendra Chaturvedi, Timothy Mcguire, Santharam Joshi, Graham Sharp, Kishor Bhakat, Angie Rizzino |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Cancer Research. 79:2892-2892 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Medulloblastoma (MB) is the most common malignant brain tumor in children that arises from cerebellar neuronal progenitor cells. Post-surgical radiotherapy in combination with adjuvant chemotherapy are considered as standard treatment of care for MB. However, this long-term treatment often leads to harmful neurologic effects to the developing brain in children. Therefore, identification of novel therapeutic target to increase efficacy and reduce toxicity in MB represent an unmet clinical need. Signal transducers and activators of transcription-3 (STAT3) is constitutively activated in MB, where it functions as an oncoprotein, mediating cancer cell proliferation. Here, to evaluate the biological consequences of specific targeting of STAT3 in detail, we engineered MYC expressing Group 3 MB cells to stably express STAT3 shRNA under a doxycycline (Dox) inducible promoter and assessed the its effect on STAT3 function. Treatment of MB cells with Dox leads to growth inhibition and cell cycle arrest. Dox treatment downregulated expression of STAT3 and its target genes/proteins including MYC and delayed migration of MB cells. Expression of STAT3 shRNA decreased association of STAT3, BRD4, phospho-RNA Pol II to the proximal promoter of MYC and CCND1. It further downregulated occupancy of acetylated histone H3 K27 to the MYC and CCND1 promoter indicating gene repression. Moreover, we showed that combination Dox and cisplatin significantly decreased highly aggressive MYC-amplified MB cell growth and induced apoptosis by downregulating STAT3 regulated proliferation and anti-apoptotic gene expression. Together, our results revealed an important role of STAT3 in regulating MB pathogenesis. Disruption of this pathway with STAT3 inhibitor, therefore, may serves as a promising candidate for targeted MB therapy by enhancing chemo-sensitivity of MB cells, potentially improving outcomes in high-risk patients. Citation Format: Sutapa Ray, Donald Coulter, Phillip Wilder, Jason Sughroue, Nagendra Chaturvedi, Timothy Mcguire, Santharam Joshi, Graham Sharp, Kishor Bhakat, Angie Rizzino. Genetic inhibition of STAT3 increases medulloblastoma chemosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2892. |
| Databáze: | OpenAIRE |
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