Molecular mechanism of adenomatous polyposis coli-induced blockade of base excision repair pathway in colorectal carcinogenesis.
Colorectal cancer (CRC) is the third leading cause of death in both men and women in North America. Despite chemotherapeutic efforts, CRC is associated with a high degree of morbidity and mortality. Thus, to develop effective treatment strategies for CRC, one needs knowledge of the pathogenesis of cancer development and cancer resistance. It is suggested that colonic tumors or cell lines harbor truncated adenomatous polyposis coli (APC) without DNA repair inhibitory (DRI)-domain. It is also thought that the product of the APC gene can modulate base excision repair (BER) pathway through an interaction with DNA polymerase β (Pol-β) and flap endonuclease 1 (Fen-1) to mediate CRC cell apoptosis. The proposed therapy with temozolomide (TMZ) exploits this particular pathway; however, a high percentage of colorectal tumors continue to develop resistance to chemotherapy due to mismatch repair (MMR)-deficiency. In the present communication, we have comprehensively reviewed a critical issue that has not been addressed previously: a novel mechanism by which APC-induced blockage of single nucleotide (SN)- and long-patch (LP)-BER play role in DNA-alkylation damage-induced colorectal carcinogenesis.
Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610 United States. Electronic address: snarayan@ufl.edu.
Satya
S
Narayan
Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610 United States.
Ritika
R
Sharma
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D025601:Adenomatous Polyposis Coli Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019951:DNA Polymerase beta / Q000032:analysis / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D045585:Flap Endonucleases / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009154:Mutation; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000077204:Temozolomide
D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; D003606:Dacarbazine; D019951:DNA Polymerase beta; D045585:Flap Endonucleases; D000077204:Temozolomide
Adenomatous polyposis coli; Base excision repair; Colorectal carcinogenesis; DNA damage