CXCL12–CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy

Abstract

Background:Pancreatic cancer cells are highly resistant to drug therapy; however, underlying causes remain largely unknown. We hypothesised that the activation of CXCL12–CXCR4 signalling confers drug resistance to pancreatic cancer cells by potentiating survival. CXCR4 is overexpressed in precancerous/malignant pancreatic lesions and cancer stem cells, and implicated in its pathogenesis.Methods:Effect of CXCR4 activation by CXCL12 on restricting the gemcitabine-induced cytotoxicity and stimulating the survival signalling was examined in pancreatic cancer cells by MTT, DNA laddering, caspase activity, immunoblot, and promoter-reporter assays. Subsequently, we examined the effect of CXCR4 antagonist, AMD3100, in abrogating the rescue effect of activated CXCL12–CXCR4 signalling.Results:The pancreatic cancer cells treated with gemcitabine exhibited reduced cytotoxicity in the presence of CXCL12 as compared with the cells treated with drug alone. CXCL12 induced the activation of FAK, ERK, and Akt signalling pathways, enhanced transcriptional activities of β-catenin and NF-κB, and expression of survival proteins. AMD3100 arrested the CXCL12-induced pancreatic cancer cell growth and drug resistance.Conclusion:Our findings demonstrate, for the first time, a role of CXCL12–CXCR4 signalling axis in conferring drug resistance to pancreatic cancer cells and suggest that it could serve as a novel therapeutic target for pancreatic cancer therapy, alone and in combination with the cytotoxic drug.

Galectin-1 Upregulates CXCR4 to Promote Tumor Progression and Poor Outcome in Kidney Cancer

“…43,44 Gal-1 also mediates chemoresistance and radioresistance in melanoma and cervical cancer cells, respectively. 15,45 Because Gal-1 is an important upstream regulator of ERK, NF-kB, and CXCR4, targeting Gal-1 may be a more effective strategy for combination cancer therapy.…”

GPCRs and cancer

“…CXCR4 is capable of orchestrating a complex signaling network, including the up-regulation of E-cadherin and c-myc as well as the modulation of molecules facilitating mammary epithelia cell transformation [85] . Enhanced CXCR4 signaling was also involved in the resistance to endocrine therapy in breast cancer [86] and in the drug resistance of colon [87] and pancreatic cancer cells [88] . Of note, CXCR4 expression and phosphorylation has been considered a negative prognostic marker in various types of cancer including acute myelogenous leukemia and B-acute lymphoblastic leukemia, breast and colon carcinomas, as it correlated with worse prognosis and decreased survival of patients [86,[89][90][91][92] .…”

Effect of CXCR4 inhibitor AMD3100 on alkaline phosphatase activity and mineralization in osteoblastic MC3T3-E1 cells

“…AMD3100 (plerixafor), a CXCR4 antagonist, which can inhibit binding of SDF-1 to CXCR4 and subsequent signal transduction, has been used as an effective hematopoietic stem cell mobilization agent in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) (5)(6)(7)(8). It has been proposed that AMD3100 may also play an important role in treatment of many other SDF-1/CXCR4-regulated pathological processes such as cancer, human immunodeficiency virus infection, rheumatoid arthritis, atherosclerosis, and asthma (9)(10)(11)(12)(13).…”