title: RhoA regulates resistance to irinotecan by regulating membrane transporter and apoptosis signaling in colorectal cancer.
abstract: Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. While surgery remains the mainstay of treatment in early stage CRC, chemotherapy is usually given to prolong the overall survival and improve the quality of life for metastatic colorectal cancer (mCRC). But drug resistance is one of the major hurdles of mCRC treatment, and the underlying mechanisms are still largely unknown. In this study, we show that, compared with parental cells, RhoA is up-regulated in irinotecan (CPT-11)-resistant CRC cells. Furthermore, inhibition of RhoA in drug resistant cells, at least partially, rescues the resistance against irinotecan and increases the sensitivity to other chemotherapeutic drug by inhibiting expression of MDR1, MRP1and GSTP1, promotes apoptosis by suppressing the expression of BCL-XL and Bcl-2 and increasing Bax expression, and significantly decreases side population cells. Our results suggest that, in addition to survival, proliferation, migration, adhesion, cell cycle and gene transcription, RhoA is also involved in chemoresistance by regulating the expression of membrane transporter and apoptosis protein in colorectal cancer. They raise an interesting possibility that the expression of RhoA may indicate a poor prognosis due to the high probability to therapy resistance and, on the other hand, inhibition of RhoA activity and function may overcome chemoresistance and improve the effectiveness of clinical treatment of CRC.
authors.affiliation: Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Ruihua
authors.affiliation: Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Mengyi
authors.affiliation: Department of Radiotherapy, The Tumor Hospital of Chengdu/The Seventh Peoples's Hospital of Chengdu, Chengdu, Sichuan Province, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chong
authors.affiliation: Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Ma
authors.initials: M
authors.lastname: Xin
authors.affiliation: Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Tang
authors.initials: T
authors.lastname: Qiulin
authors.affiliation: Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Bi
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Ming
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077146:Irinotecan; D026901:Membrane Transport Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D051020:bcl-X Protein / Q000032:analysis; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D026901:Membrane Transport Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C066737:RHOA protein, human; D000077146:Irinotecan; D020742:rhoA GTP-Binding Protein; D002166:Camptothecin
keywords: RhoA; chemoresistance; colorectal cancer; irinotecan