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Antagonizing CDK8 Sensitizes Colorectal Cancer to Radiation Through Potentiating the Transcription of e2f1 Target Gene apaf1.

ABSTRACT: Radiotherapy is an essential curative treatment modality for colorectal cancer. Apoptosis is the major mechanism of IR-induced cell death and aberrant apoptotic signaling results in radioresistance, which is a hallmark of most, perhaps all, types of human cancers. Potentiating the induction of apoptosis is an emerging strategy for cancer radiotherapy. Here, we determined that targeting CDK8 selectively radiosensitized colorectal cancer through the mitochondria-dependent intrinsic apoptotic signaling, which was mediated through the induction of the transcription of apaf1 that was e2f1- and not p53-dependent. Importantly, the enhanced transcriptional activity of e2f1 was dependent on the kinase activity of CDK8 itself and not on the assembling of the mediator complex. In addition, clinical inhibitor, and in vivo studies confirmed the radiosensitizing effect of CDK8. Our results provide a new targeting strategy to improve the radiotherapy of CRC.

SUBMITTER: Chen B

PROVIDER: S-EPMC7304162 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Antagonizing CDK8 Sensitizes Colorectal Cancer to Radiation Through Potentiating the Transcription of e2f1 Target Gene apaf1.

Chen Bin B Wen Pengbo P Hu Guanshuo G Gao Yang Y Qi Xiaojing X Zhu Kaili K Chen Shaopeng S Wu Lijun L Xu An A Zhao Guoping G

Frontiers in cell and developmental biology 20200612

Radiotherapy is an essential curative treatment modality for colorectal cancer. Apoptosis is the major mechanism of IR-induced cell death and aberrant apoptotic signaling results in radioresistance, which is a hallmark of most, perhaps all, types of human cancers. Potentiating the induction of apoptosis is an emerging strategy for cancer radiotherapy. Here, we determined that targeting CDK8 selectively radiosensitized colorectal cancer through the mitochondria-dependent intrinsic apoptotic signa ...[more]

PMID: 32596239

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Project description:Radiation therapy is the primary intervention for nearly half of the patients with localized advanced prostate cancer and standard of care for recurrent disease following surgery. The development of radiation-resistant disease is an obstacle for nearly 30-50% of patients undergoing radiotherapy. A better understanding of mechanisms that lead to radiation resistance could aid in the development of sensitizing agents to improve outcome. Here we identified a radiation-resistance pathway mediated by CD105, downstream of BMP and TGF-? signaling. Antagonizing CD105-dependent BMP signaling with a partially humanized monoclonal antibody, TRC105, resulted in a significant reduction in clonogenicity when combined with irradiation. In trying to better understand the mechanism for the radio-sensitization, we found that radiation-induced CD105/BMP signaling was sufficient and necessary for the upregulation of sirtuin 1 (SIRT1) in contributing to p53 stabilization and PGC-1? activation. Combining TRC105 with irradiation delayed DNA damage repair compared to irradiation alone. However, in the absence of p53 function, combining TRC105 and radiation resulted in no reduction in clonogenicity compared to radiation alone, despite similar reduction of DNA damage repair observed in p53-intact cells. This suggested DNA damage repair was not the sole determinant of CD105 radio-resistance. As cancer cells undergo an energy deficit following irradiation, due to the demands of DNA and organelle repair, we examined SIRT1's role on p53 and PGC-1? with respect to glycolysis and mitochondrial biogenesis, respectively. Consequently, blocking the CD105-SIRT1 axis was found to deplete the ATP stores of irradiated cells and cause G2 cell cycle arrest. Xenograft models supported these findings that combining TRC105 with irradiation significantly reduces tumor size over irradiation alone (p value?=?10-9). We identified a novel synthetic lethality strategy of combining radiation and CD105 targeting to address the DNA repair and metabolic addiction induced by irradiation in p53-functional prostate cancers.

Dataset Information

Antagonizing CDK8 Sensitizes Colorectal Cancer to Radiation Through Potentiating the Transcription of e2f1 Target Gene apaf1.

Publications

Antagonizing CDK8 Sensitizes Colorectal Cancer to Radiation Through Potentiating the Transcription of e2f1 Target Gene apaf1.

Similar Datasets

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