Mitochondrial topoisomerase I promotes tumor growth

Identification: Baechler, Andrea Simone


Description

Mitochondrial topoisomerase I promotes tumor growth
 
Baechler SA1, Factor VM1, Ravji A1, Marquardt JU2, Becker D2, Huang SY1, Zhang H1, Pommier Y1
1Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, USA
2Department of Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
 
Mitochondria play a key role in empowering cancer cell survival in a highly challenging microenvironment by ensuring biosynthetic and bioenergetics supply. Therefore, developing therapeutic interventions targeting mitochondria has become an emerging field of interest. The nuclear encoded mitochondrial topoisomerase I (TOP1MT) has been shown to be critical for maintenance of mitochondrial DNA integrity by releasing topological stress. TOP1MT is highly upregulated in colon and hepatocellular carcinomas. Further, patients with high expression of the TOP1MT gene have a poor survival prognosis (TCGA database) which led us to address a role of TOP1MT in carcinogenesis.
In a xenograft model using human colon carcinoma cells (HCT116 WT/ TOP1MT KO), we observed significantly slower tumor growth in the absence of TOP1MT. In line with our hypothesis, steady-state levels of ATP as well as building blocks were decreased in tumors lacking TOP1MT due to impaired mitochondrial respiratory activity. TOP1MT-deficient tumors showed a significant reduction of the amount of respiratory chain proteins, despite an increase in mitochondrial transcript levels. To extend our findings to an intrinsic carcinogenesis model, we induced hepatocellular carcinomas (HCCs) in WT and TOP1MT KO neonate mice using a combination of a single dose of diethylnitrosamine followed by repeated injections of carbon tetrachloride for cancer promotion. Lack of TOP1MT led to significantly diminished tumor burden, decreased maximal tumor size and reduced multiplicity compared to the WT littermates. Cluster analysis of mouse tumor samples and 53 human HCCs revealed a significant correlation of TOP1MT gene expression signature with patient prognosis.
Together, our results demonstrate that loss of TOP1MT suppresses tumor growth in both a xenograft and chemically induced carcinogenesis model. We conclude that TOP1MT is important for cancer cell growth in nutritionally compromised microenvironments, in which cells become sensitive to disturbances of mitochondrial function. Our study identifies TOP1MT as a putative mitochondrial target for cancer therapy.
 

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