The Association of CXC Receptor 4 Mediated Signaling Pathway with Oxaliplatin-Resistant Human Colorectal Cancer Cells.
The stromal cell-derived factor-1 (SDF-1)/CXC receptor 4 (CXCR4) axis plays an important role in tumor angiogenesis and invasiveness in colorectal cancer (CRC) progression. In addition, metastatic CRC remains one of the most difficult human malignancies to treat because of its chemoresistant behavior. However, the mechanism by which correlation occurs between CXCR4 and the clinical response of CRC to chemotherapy remains unknown. We generated chemoresistant cells with increasing doses of oxaliplatin (OXA) and 5-Fluorouracil (5FU) to develop resistance at a clinical dose. We found that the putative markers did not change in the parental cells, but HCT-116/OxR and HCT-116/5-FUR were more aggressive and had higher tumor growth (demonstrated by wound healing, chemotaxis assay, and a nude mice xenograft model) with the use of oxaliplatin. Apoptosis induced by oxaliplatin treatment was significantly decreased in HCT-116/OxR compared to the parental cells. Moreover, HCT-116/OxR cells displayed increased levels of p-gp, p-Akt p-ERK, p-IKBβ, CXCR4, and Bcl-2, but they also significantly inhibited the apoptotic pathways when compared to the parental strain. We evaluated the molecular mechanism governing the signaling pathway associated with anti-apoptosis activity and the aggressive status of chemoresistant cells. Experiments involving specific inhibitors demonstrated that the activation of the pathways associated with CXCR4, ERK1/2 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt is critical to the functioning of the HCT-116/OxR and HCT-116/5-FUR characteristics of chemosensitivity. These findings elucidate the mechanism of CXCR4/PI3K/Akt downstream signaling and provide strategies to inhibit CXCR4 mediated signaling pathway in order to overcome CRC's resistance to chemotherapy.
Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Chang Gung University College of Medicine, Taoyuan, Taiwan.
Wen-Shih
WS
Huang
Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Chiayi, Taiwan.
Meng-Chiao
MC
Hsieh
Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Chiayi, Taiwan.
Cheng-Yi
CY
Huang
Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Chiayi, Taiwan.
Yi-Hung
YH
Kuo
Department of Hepato-Gastroenterological, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Chang Gung University College of Medicine, Taoyuan, Taiwan.
Shui-Yi
SY
Tung
Department of Hepato-Gastroenterological, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Chiayi, Taiwan.
Chien-Heng
CH
Shen
Department of Hepato-Gastroenterological, Chang Gung Memorial Hospital, Chiayi, Taiwan.
Yung-Yu
YY
Hsieh
Institute of Nursing and Department of Nursing, Chang Gung Institute of Technology Chiayi Campus, Chiayi, Taiwan.
Chih-Chuan
CC
Teng
Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Taiwan.
Kam-Fai
KF
Lee
Division of Nephrology Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Te-Chuan
TC
Chen
Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Ko-Chao
KC
Lee
Institute of Nursing and Department of Nursing, Chang Gung Institute of Technology Chiayi Campus, Chiayi, Taiwan.|Chronic Diseases and Health Promotion Research Center, CGUST, Chiayi, Taiwan.|Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
Hsing-Chun
HC
Kuo
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