IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1)

Abstract

Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.

Identification of Intestinal Flora-Related Key Genes and Therapeutic Drugs in Colorectal Cancer

“…Another cytokine, CXCL8, has been proven to be associated with chemoresistance of CRC [27]. The increased expression of CXCL8 induced by anti-cancer drugs, such as doxorubicin and cisplatin, can upregulate the expression of ATP-binding cassette transporters, resulting in poor chemotherapeutic response [27]. Moreover, a high level of CXCL8 predicted poor overall survival in patients with CRC [28], which is contrary to our ndings in this study.…”

“…Yet in the tumor microenvironment, CSF2 is often up-regulated and suppress the immune response, resulting in a poor prognosis for patients [25,26]. Another cytokine, CXCL8, has been proven to be associated with chemoresistance of CRC [27]. The increased expression of CXCL8 induced by anti-cancer drugs, such as doxorubicin and cisplatin, can upregulate the expression of ATP-binding cassette transporters, resulting in poor chemotherapeutic response [27].…”

Identification of intestinal flora-related key genes and therapeutic drugs in colorectal cancer

“…Another cytokine, CXCL8, has been proven to be associated with chemoresistance of CRC [29]. The increased expression of CXCL8 induced by anti-cancer drugs, such as doxorubicin and cisplatin, can upregulate the expression of ATP-binding cassette transporters, resulting in poor chemotherapeutic response [29]. Moreover, a high level of CXCL8 predicted poor overall survival in patients with CRC [30], which is contrary to our ndings in this study.…”

Identification of Hub Genes Related to Carcinogenesis and Prognosis in Colorectal Cancer Based on Integrated Bioinformatics

“…On the contrary, overexpression of CXCL8 promoted proliferation, migration, and invasion of CRC cells, which was strongly correlated with CRC angiogenesis, metastasis, poor prognosis, and disease-free survival [44,45]. However, high expression of CXCL8 could act as a protective barrier for liver metastasis of CRC and coincide with better prognosis [46,47]. Objectively, the role of CXCL8 still remained in dispute.…”