TY - JOUR
T1 - RAD51AP1 loss attenuates colorectal cancer stem cell renewal and sensitizes to chemotherapy
AU - Bridges, Allison E.
AU - Ramachandran, Sabarish
AU - Tamizhmani, Kavin
AU - Parwal, Utkarsh
AU - Lester, Adrienne
AU - Rajpurohit, Pragya
AU - Morera, Daley S.
AU - Hasanali, Sarrah L.
AU - Arjunan, Pachiappan
AU - Jedeja, Ravirajsinh N.
AU - Patel, Nikhil
AU - Martin, Pamela M.
AU - Korkaya, Hasan
AU - Singh, Nagendra
AU - Manicassamy, Santhakumar
AU - Prasad, Puttur D.
AU - Lokeshwar, Vinata B.
AU - Lokeshwar, Bal L.
AU - Ganapathy, Vadivel
AU - Thangaraju, Muthusamy
N1 - Funding Information:
We thank Penny P. Roon, Donna Kumiski, and Dr. Brendan Marshall, Electron Microscopy and Histology Core facility, Augusta University Cancer Center, for their help in histological analysis. This work was supported by Augusta University Intramural Pilot PSRP Award, Start-up and Bridge funding (to M. Thangaraju) and National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) R01DK123360 grant (to S. Manicassamy).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/9
Y1 - 2021/9
N2 - DNA damage, induced by either chemical carcinogens or environmental pollutants, plays an important role in the initiation of colorectal cancer. DNA repair processes, however, are involved in both protecting against cancer formation, and also contributing to cancer development, by ensuring genomic integrity and promoting the efficient DNA repair in tumor cells, respectively. Although DNA repair pathways have been well exploited in the treatment of breast and ovarian cancers, the role of DNA repair processes and their therapeutic efficacy in colorectal cancer is yet to be appreciably explored. To understand the role of DNA repair, especially homologous recombination (HR), in chemical carcinogen-induced colorectal cancer growth, we unraveled the role of RAD51AP1 (RAD51-associated protein 1), a protein involved in HR, in genotoxic carcinogen (azoxymethane, AOM)-induced colorectal cancer. Although AOM treatment alone significantly increased RAD51AP1 expression, the combination of AOM and dextran sulfate sodium (DSS) treatment dramatically increased by several folds. RAD51AP1 expression is found in mouse colonic crypt and proliferating cells. RAD51AP1 expression is significantly increased in majority of human colorectal cancer tissues, including BRAF/KRAS mutant colorectal cancer, and associated with reduced treatment response and poor prognosis. Rad51ap1-deficient mice were protected against AOM/DSS-induced colorectal cancer. These observations were recapitulated in a genetically engineered mouse model of colorectal cancer (ApcMin/+). Furthermore, chemotherapy-resistant colorectal cancer is associated with increased RAD51AP1 expression. This phenomenon is associated with reduced cell proliferation and colorectal cancer stem cell (CRCSC) self-renewal. Overall, our studies provide evidence that RAD51AP1 could be a novel diagnostic marker for colorectal cancer and a potential therapeutic target for colorectal cancer prevention and treatment. Implications: This study provides first in vivo evidence that RAD51AP1 plays a critical role in colorectal cancer growth and drug resistance by regulating CRCSC self-renewal.
AB - DNA damage, induced by either chemical carcinogens or environmental pollutants, plays an important role in the initiation of colorectal cancer. DNA repair processes, however, are involved in both protecting against cancer formation, and also contributing to cancer development, by ensuring genomic integrity and promoting the efficient DNA repair in tumor cells, respectively. Although DNA repair pathways have been well exploited in the treatment of breast and ovarian cancers, the role of DNA repair processes and their therapeutic efficacy in colorectal cancer is yet to be appreciably explored. To understand the role of DNA repair, especially homologous recombination (HR), in chemical carcinogen-induced colorectal cancer growth, we unraveled the role of RAD51AP1 (RAD51-associated protein 1), a protein involved in HR, in genotoxic carcinogen (azoxymethane, AOM)-induced colorectal cancer. Although AOM treatment alone significantly increased RAD51AP1 expression, the combination of AOM and dextran sulfate sodium (DSS) treatment dramatically increased by several folds. RAD51AP1 expression is found in mouse colonic crypt and proliferating cells. RAD51AP1 expression is significantly increased in majority of human colorectal cancer tissues, including BRAF/KRAS mutant colorectal cancer, and associated with reduced treatment response and poor prognosis. Rad51ap1-deficient mice were protected against AOM/DSS-induced colorectal cancer. These observations were recapitulated in a genetically engineered mouse model of colorectal cancer (ApcMin/+). Furthermore, chemotherapy-resistant colorectal cancer is associated with increased RAD51AP1 expression. This phenomenon is associated with reduced cell proliferation and colorectal cancer stem cell (CRCSC) self-renewal. Overall, our studies provide evidence that RAD51AP1 could be a novel diagnostic marker for colorectal cancer and a potential therapeutic target for colorectal cancer prevention and treatment. Implications: This study provides first in vivo evidence that RAD51AP1 plays a critical role in colorectal cancer growth and drug resistance by regulating CRCSC self-renewal.
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U2 - 10.1158/1541-7786.MCR-20-0780
DO - 10.1158/1541-7786.MCR-20-0780
M3 - Article
C2 - 34099522
AN - SCOPUS:85114168489
SN - 1541-7786
VL - 19
SP - 1486
EP - 1497
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 9
ER -
