Downregulation of Foxc2 enhances apoptosis induced by 5-fluorouracil through activation of MAPK and AKT pathways in colorectal cancer

Yang, Chao; Cui, Xiaoxian; Dai, Xiaoqin; Liao, Wenting

doi:10.3892/ol.2016.4097

Cited by 23 publications

(20 citation statements)

References 30 publications

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“…23,24 As we observed, the sensitivity of MDA-MB-231/CR cells to DOX, TRAIL, and 5-FU was also reduced significantly compared with their parental MDA-MB-231 cells. And similarly, we found the MDA-MB-231/DR cells were resistant to CDDP, TRAIL, and 5-FU (Figure3(a)).…”

Section: Cross-resistance Of Trail and 5-fu In The Cddp/dox-resistantsupporting

confidence: 56%

Chemoresistance is associated with overexpression of HAX-1, inhibition of which resensitizes drug-resistant breast cancer cells to chemotherapy

Yang

Wang

et al. 2017

Tumour Biol.

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Acquired resistance to standard chemotherapy is the common and critical limitation for cancer therapy. Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) has been reported to be upregulated in numerous cancers. However, the role of HAX-1 in oncotherapy remains unclear. In this study, we established MDA-MB-231 cell lines which were resistant to cisplatin (MDA-MB-231/CR) or doxorubicin (MDA-MB-231/DR) to study the chemoresistance in breast cancer. As a result, the HAX-1 which is an apoptosis-associated protein was observed to be overexpressed in both MDA-MB-231/CR and MDA-MB-231/DR compared with the routine MDA-MB-231 cells. Moreover, knockdown of HAX-1 via RNA interference decreased IC50 level of cisplatin by 70.91% in MDA-MB-231/CR cells, and the IC50 level of doxorubicin was decreased by 76.46% in MDA-MB-231/DR cells when the HAX-1 was downregulated. Additionally, we found that the knockdown of HAX-1 induced the release of cytochrome C from mitochondria, resulting in the activation of caspases. Taken together, our study indicates that the overexpression of HAX-1 is essential in the development of chemoresistance in breast cancer. Furthermore, we identify that HAX-1 may become the target for cancer therapy.

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Section: Cross-resistance Of Trail and 5-fu In The Cddp/dox-resistantsupporting

confidence: 56%

Chemoresistance is associated with overexpression of HAX-1, inhibition of which resensitizes drug-resistant breast cancer cells to chemotherapy

Yang

Wang

et al. 2017

Tumour Biol.

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“…It has also been shown to drive osteosarcoma metastasis to lung tissue via a CXCR4-dependent mechanism (26). A large body of evidence has also recently demonstrated that FOXC2 promotes drug resistance in various cancer types, including osteosarcoma, nasopharyngeal carcinoma, and non-small cell lung, prostate, ovarian, colorectal, and basal-like breast cancers (16,18,19,(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

“…proliferation, epithelial-mesenchymal transition (EMT), metastatic behavior, and drug resistance (10,11,(15)(16)(17)(18)(19). Despite the significance of these oncogenic functions of FOXC2, however, much remains to be learned about the mechanisms underlying their induction.…”

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confidence: 99%

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness

Hargadon

Győrffy

Strong

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: The FOXC2 transcription factor promotes the progression of several cancer types, but has not been investigated in the context of melanoma cells. To study FOXC2's influence on melanoma progression, we generated a FOXC2-deficient murine melanoma cell line and evaluated The Cancer Genome Atlas (TCGA) patient datasets. Materials and Methods: We compared tumor growth kinetics and RNA-seq/qRT-PCR gene expression profiles from wild-type versus FOXC2-deficient murine melanomas. We also performed Kaplan-Meier survival analysis of TCGA data to assess the influence of FOXC2 gene expression on melanoma patients' response to chemotherapy and immunotherapy. Results: FOXC2 promotes melanoma progression and regulates the expression of genes associated with multiple oncogenic pathways, including the oxidative stress response, xenobiotic metabolism, and interferon responsiveness. FOXC2 expression in melanoma correlates negatively with patient response to chemotherapy and immunotherapy. Conclusion: FOXC2 drives a tumor-promoting gene expression program in melanoma and is a prognostic indicator of patient response to multiple cancer therapies. Melanoma, a highly aggressive form of cancer arising from pigment-producing melanocytes, is responsible for the majority of skin cancer-related mortality, accounting for~6 0,000 annual deaths worldwide (1). Importantly, the incidence of melanoma has risen substantially over the last 40 years (2), a trend that is expected to continue to at least 2031 (3). Although surgical removal of primary lesions is typically successful in the treatment of early-stage disease, many melanoma patients are not diagnosed until later stages of metastatic disease in which surgery is either not possible or largely ineffective. Unfortunately, malignant melanoma is highly resistant to radiation and chemotherapy, and the only FDA-approved chemotherapeutic for the treatment of melanoma, dacarbazine (DTIC), has a minimal impact on patient survival (4). While advances in targeted therapy and immunotherapy have improved the prognosis for melanoma in recent years, there are still patients who do not respond to these regimens, and relapse of therapy-resistant tumors remains an ongoing challenge in many patients who do achieve clinical benefit (5, 6). Therefore, in order to improve the clinical outcome of melanoma patients going forward, it is necessary to gain additional insight into factors that promote melanoma progression and resistance to these therapeutic modalities. FOXC2 is a member of the forkhead box family of transcription factors that control a variety of cellular processes in embryonic and adult tissues. In addition to its normal regulation of development, growth, and metabolism in various tissue types, FOXC2 has recently emerged as a driver of several hallmarks of cancer progression as well. Within vascular endothelial cells, FOXC2 promotes expression of multiple genes that enhance angiogenesis (7-9). FOXC2 can also become overexpressed or dysregulated in tumor cells themselves, where it is asso...

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“…Zhou et al showed that FOXC2 could promote chemoresistance in nasopharyngeal carcinomas via induction of epithelial mesenchymal transition [31]. Also, Yang et al reported that downregulation of Foxc2 could enhance apoptosis induced by 5-fluorouracil in colorectal cancer [32]. Although overexpressed FOXC2 is reported to enhance the epithelial-to-mesenchymal transition and invasion of ovarian cancer cells, the roles of FOXC2 in the development of CDDP resistance in ovarian cancer cells is unclear and needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Also, FOXC2 enhanced AKT activity with subsequent GSK-3β phosphorylation and Snail stabilization, and then induced EMT and promoted tumor invasion and metastasis in colorectal cancer [34]. Yang et al showed that downregulation of FOXC2 could enhance 5-fluorouracil-inducing apoptosis through activation of MAPK and AKT pathways in colorectal cancer [32]. However, whether FOXC2 promotes the chemoresistance of ovarian cancer cells to CDDP by activation of Akt and MAPK signaling pathways is unknown.…”

Section: Discussionmentioning

confidence: 99%

Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

Ding

Tian

et al. 2016

Cell Physiol Biochem

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Background/Aims: FOXC2 has been reported to play a role in tumor progression, but the correlations of FOXC2 with the cisplatin (CDDP) resistance of ovarian cancer cells are still unclear. The purpose of the present study is to investigate the roles of FOXC2 in the CDDP resistance of ovarian cancer cells and its possible mechanisms. Methods: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of FOXC2 mRNA in CDDP-resistant or sensitive ovarian cancer tissues and cell lines (SKOV3/CDDP and SKOV3). Gain- and loss-of-function assays were performed to analyze the effects of FOXC2 knockdown or overexpression on the in vitro and in vivo sensitivity of ovarian cancer cells to CDDP and its possible molecular mechanisms. Results: The relative expression level of FOXC2 mRNA in CDDP-resistant ovarian cancer tissues was higher than that in CDDP-sensitive tissues. Also, the expression of FOXC2 mRNA and protein in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) cell line was higher than that in its parental cell line (SOKV3). Small hairpin RNA (shRNA)-mediated FOXC2 knockdown significantly increased the in vitro and in vive sensitivity of SKOV3/CDDP cells to CDDP by enhancing apoptosis, while upregulation of FOXC2 significantly decreased the in vitro and in vivo sensitivity of SKOV3 cells to CDDP by reducing apoptosis. Furthermore, FOXC2 activates the Akt and MAPK signaling pathways, and then induced the decreased expression of Bcl-2 protein and the increased expression of Bax and cleaved caspase-3 proteins. Conclusions: FOXC2 mediates the CDDP resistance of ovarian cancer cells by activation of the Akt and MAPK signaling pathways, and may be a potential novel therapeutic target for overcoming CDDP resistance in human ovarian cancer.

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Downregulation of Foxc2 enhances apoptosis induced by 5-fluorouracil through activation of MAPK and AKT pathways in colorectal cancer

Cited by 23 publications

References 30 publications

Chemoresistance is associated with overexpression of HAX-1, inhibition of which resensitizes drug-resistant breast cancer cells to chemotherapy

Chemoresistance is associated with overexpression of HAX-1, inhibition of which resensitizes drug-resistant breast cancer cells to chemotherapy

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness

Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

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