Downregulation of DNA repair proteins and increased DNA damage in hypoxic colon cancer cells is a therapeutically exploitable vulnerability
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Jennifer M. J. Jongen1, Lizet M. van der Waals1, Kari Trumpi1, Jamila Laoukili1, Niek A. Peters1, Susanne J. Schenning-van Schelven1, Klaas M. Govaert1, Inne H. M. Borel Rinkes1 and Onno Kranenburg1,2
1UMC Utrecht, Cancer Center, 3584CX Utrecht, The Netherlands
2UMC Utrecht Division of Biomedical Genetics, 3584CX Utrecht, The Netherlands
Onno Kranenburg, email: [email protected]
Keywords: DNA repair, colon cancer, DNA damage, Tirapazamine, cancer stem cells
Received: March 29, 2017 Accepted: August 04, 2017 Published: September 21, 2017
Surgical removal of colorectal cancer (CRC) liver metastases generates areas of tissue hypoxia. Hypoxia imposes a stem-like phenotype on residual tumor cells and promotes tumor recurrence. Moreover, in primary CRC, gene expression signatures reflecting hypoxia and a stem-like phenotype are highly expressed in the aggressive Consensus Molecular Subtype 4 (CMS4). Therapeutic strategies eliminating hypoxic stem-like cells may limit recurrence following resection of primary tumors or metastases.
Here we show that expression of DNA repair genes is strongly suppressed in CMS4 and inversely correlated with hypoxia-inducible factor-1 alpha (HIF1α) and HIF-2α co-expression signatures. Tumors with high expression of HIF signatures and low expression of repair proteins showed the worst survival. In human tumors, expression of the repair proteins RAD51, KU70 and RIF1 was strongly suppressed in hypoxic peri-necrotic tumor areas. Experimentally induced hypoxia in patient derived colonospheres in vitro or in vivo (through vascular clamping) was sufficient to downregulate repair protein expression and caused DNA damage. Hypoxia-induced DNA damage was prevented by expressing the hydroperoxide-scavenging enzyme glutathione peroxidase-2 (GPx2), indicating that reactive oxygen species mediate hypoxia-induced DNA damage. Finally, the hypoxia-activated prodrug Tirapazamine greatly augmented DNA damage and reduced the fraction of stem-like (Aldefluorbright) tumor cells in vitro, and in vivo following vascular clamping.
We conclude that decreased expression of DNA repair proteins and increased DNA damage in hypoxic tumor areas may be therapeutically exploited with hypoxia-activated prodrugs, and that such drugs reduce the fraction of Aldefluorbright (stem-like) tumor cells.
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