Visfatin inhibits colon cancer cell apoptosis and decreases chemosensitivity to 5‑FU by promoting the SDF‑1/CXCR4/Akt axis

Abstract

5-Fluorouracil (5-FU) is the preferred chemotherapeutic drug used in the treatment of colon cancer; however, drug resistance affects its clinical efficacy. Visfatin, an adipokine that promotes tumour development, has the potential to increase resistance to chemotherapy. The present study aimed to verify the effects of visfatin on the sensitivity of colon cancer cells to 5-FU and to elucidate the potential mechanisms involved. Tissue microarrays (TMAs) were used to analyse visfatin differential expression in normal colon and colon cancer tissues, and the data were further validated in vitro . Cell Counting Kit-8, clone formation, caspase-3/7 activity assays, as well as other analyses were used to verify the effects of visfatin on sensitivity to 5-FU. TMA and correlation analyses were used to predict and verify the correlation between visfatin and stromal cell-derived factor-1 (SDF-1). Rescue experiments and PI3K/Akt inhibitors were used to verify the role of the visfatin/SDF-1/Akt axis in the sensitivity of colon cancer cells to 5-FU. Visfatin was found to be highly expressed in colon cancer tissues and cell lines. Moreover, visfatin knockdown increased apoptosis, reduced cell proliferation and enhanced the chemosensitivity of DLD-1 and SW48 cells to 5-FU. A positive correlation between visfatin and SDF-1 was observed, with the knockdown of visfatin enhancing cell sensitivity to 5-FU chemotherapy by targeting the SDF-1/C-X-C chemokine receptor type 4 (CXCR4) axis. Furthermore, the Akt signalling pathway downstream of SDF-1/CXCR4 proved to be critical in the decreased sensitisation of colon cancer cells to 5-FU induced by visfatin. On the whole, the present study demonstrates that visatin can potentially decrease colon cancer cell apoptosis, promote proliferation and decrease colon cancer cell sensitivity to 5-FU via the visfatin/SDF-1/Akt axis.

The Effect of Visfatin on the Functioning of the Porcine Pituitary Gland: An In Vitro Study

“…Conversely, the inhibitory effect of VIS was documented in studies on mouse and rat pancreatic cell lines, rat hippocampal cells, and a colon cancer cell line [28,[30][31][32]. Furthermore, VIS was observed to exhibit an anti-apoptotic effect by increasing the gene/protein expression of Bcl-2 and decreasing the gene/protein expression of cellular tumor antigen p53 (a key regulator of apoptosis that promotes cell death after extensive DNA damage), cytochrome c (a factor that mediates activation of the intrinsic pathway of apoptosis), and caspase 3 [43,45,[47][48][49]. The results obtained in this study suggest that VIS does not trigger cell death.…”

Visfatin induces ovarian cancer resistance to anoikis by regulating mitochondrial activity

“…Wang et al [8] reported that visfatin stimulates proliferation, and inhibits apoptosis of, endometrial carcinoma in both Ishikawa and KLE cells. Furthermore, visfatin may promote proliferation and inhibit apoptosis of colon and breast cancer cells [9,19]. PARP is one of the best known substrates for caspase activity, and PARP cleavage to yield fragments of 89 and 24 kDa is a universally accepted hallmark of apoptosis [20].…”

Multi-Faceted Role of Cancer-Associated Adipocytes in Colorectal Cancer

“…Visfatin, such as leptin, is another adipokine that supports colorectal carcinogenesis through different signaling pathways activation, such as ERK1/2, p38 MAPK, PI3K/mTOR, JNK, and JAK/STAT, which promote cell proliferation and metastasis [ 79 ]. In addition, a recent study revealed that visfatin also acts as an inhibitor of the 5-fluorouracil (5-FU) therapeutic effect in CRC patients through visfatin/SDF-1/Akt pathway activation ( Table 1 ) [ 80 ].…”

“…Radical surgery associated with chemotherapy is the conventional treatment in CRC cases, 5-FU being the most common used drug in the advanced stages of the disease. Several mechanisms are currently related to 5-FU chemoresistance and treatment failure in CRC, such as Bcl-2 and Bcl-xL overexpression in cancer cells, p53 gene mutations, 5-FU efflux induced by the increased expression of the ATP-binding cassette transporter, nucleoside metabolizing enzymes overexpression, along with mismatch repair system disruption [ 80 ]. Adipocytes and CAAs-derived visfatin have been shown to reduce the sensitivity to 5-FU through SDF-1/CXCR4 pathway activation ( Table 2 ) [ 80 ].…”

“…Several mechanisms are currently related to 5-FU chemoresistance and treatment failure in CRC, such as Bcl-2 and Bcl-xL overexpression in cancer cells, p53 gene mutations, 5-FU efflux induced by the increased expression of the ATP-binding cassette transporter, nucleoside metabolizing enzymes overexpression, along with mismatch repair system disruption [ 80 ]. Adipocytes and CAAs-derived visfatin have been shown to reduce the sensitivity to 5-FU through SDF-1/CXCR4 pathway activation ( Table 2 ) [ 80 ]. This finding could lead to researchers focusing on visfatin inhibitor use in association with 5-FU to reduce chemotherapeutic drug resistance, mainly in inoperable CRC cases.…”