Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 2, Pages 786-801Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI97631
Keywords
-
Categories
Funding
- NIH [R01-CA085704, R01-CA52462, R01-CA105125, R01-CA98575, P41-EB002034, PO1-CA115675, T32-CA062948-13, R01-CA158367, R24-CA83084, P50-CA086438]
- Breast and Molecular Imaging Fund
- Evelyn H. Lauder Breast Center
- MSKCC
- Experimental Therapeutics Center of MSKCC
- William H. Goodwin, Alice Goodwin and Commonwealth Foundation for Cancer Research
- Virginia and D.K. Ludwig Fund for Cancer Research
- Larry and Stephanie Flinn Foundation
- Francois Wallace Monahan Fellowship
- NIH/National Cancer Institute Cancer Center Support Core Grant [P30-CA008748]
Ask authors/readers for more resources
Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3x9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available