Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade

Zhang, Binhao; Leng, Chao; Wu, Chao; Zhang, Zhanguo; Dou, Liping; Luo, Xin; Chen, Xiaoping

doi:10.3892/or.2015.4479

Cited by 28 publications

(19 citation statements)

References 34 publications

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“…Activation of PI3K/AKT signaling pathway in cancer results in increased cell survival, outgrowth and enhanced cell migration (25). Inhibition of its activation will downregulate expression of survivin, MMP1, 2, 3, 9, 12, 13 and MT1-MMP, thus, suppresses the proliferation, migration and invasion of cancer cells (26)(27)(28)(29)(30)(31). Our results showed that GRA treatment significantly suppresses the phosphorylation of PI3K and AKT in LoVo, SW620 and SW480 cells, and the phosphorylation of PI3K occurs as early as 2 h after GRA treatment.…”

Section: Discussionmentioning

confidence: 99%

18 β-glycyrrhetinic acid exhibits potent antitumor effects against colorectal cancer via inhibition of cell proliferation and migration

Wang

Shen

Qiu

et al. 2017

International Journal of Oncology

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Accumulating evidence shows that 18 β-glycyr-rhetinic acid (GRA) has antitumor activities in breast, ovarian cancer and leukemia, while its role in colorectal cancer remains unknown. In the present study, we investigated the effect of GRA in colorectal cancer cells LoVo, SW480 and SW620 and studied the underlying molecular mechanisms. Results showed that GRA had potent inhibitory effects on colorectal cancer cell proliferation in a dose- and time-dependent manner in vitro and in vivo. Growth inhibition was mediated by pro-apoptosis, as evident from Annexin V-FITC staining, the reduced expression of survivin and the induced expression of cleaved PARP. Furthermore, GRA treatment resulted in marked reduction of cell migration, invasion and wound healing capability, accompanying by the downregulated MMP expression. Moreover, GRA decreased the protein levels of p-PI3K, p-AKT, p-STAT3, p-JNK, p-p38 and p-NF-κB p65, of which the phosphorylation of PI3K and STAT3 decreased as early as 2 h after the GRA treatment. These results suggest that regulation of the apoptosis, invasion and migration of colorectal cancer cells by GRA might be through suppressing PI3K and STAT3 signaling pathways. the present study indicated that GRA could be a potential effective therapy for patients with colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

18 β-glycyrrhetinic acid exhibits potent antitumor effects against colorectal cancer via inhibition of cell proliferation and migration

Wang

Shen

Qiu

et al. 2017

International Journal of Oncology

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“…Survivin is also correlated with the poor prognosis of colorectal adenocarcinoma patients (13,(15)(16)(17)(18)(19). Survivin takes part in the cell apoptosis of gastric cancer cells (21,22), and is involved in cell cycle arrest in colorectal cancer (23). Increased apoptosis by a survivin inhibitor is considered as an effective treatment for colon cancer (24).…”

Section: Discussionmentioning

confidence: 99%

“…Suppression of survivin induces mitochondrial-mediated apoptosis in gastric cancer cells (21,22). In addition, survivin is involved in the cell cycle arrest of colorectal cancer cells (23). Increased apoptosis by a survivin inhibitor is considered as an effective treatment for colon cancer (24).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of PARP6 or survivin promotes cell apoptosis and inhibits cell invasion of colorectal adenocarcinoma cells

Wang

Luo

et al. 2017

Oncology Reports

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Colorectal adenocarcinoma is the third most common cancer worldwide. PARP6, a novel member of the poly(ADP-ribose) polymerases (PARPs) and survivin, a member of the family of inhibitor of apoptosis (IAP) proteins are associated with a poor prognosis in various types of cancers. However, limited evidence exists regarding the interaction between PARP6 and survivin in colorectal adenocarcinoma. In the present study, we used the paired samples of 20 patients with colorectal adenocarcinoma to detect the expression of PARP6 and survivin in both tumor and adjacent normal colorectal mucosa. Their interaction and roles in cell viability, cell cycle, cell apoptosis and cell invasion were further investigated. Our results showed that both PARP6 and survivin exhibited higher expression in colorectal adenocarcinoma tissues and SW620 cells when compared with levels in adjacent non-tumor tissues and a normal colon cell line FHC. Co-immunoprecipitation assay showed that a significant correlation existed between PARP6 and survivin. We also showed that sole treatment of PARP6 siRNA or survivin siRNA partially inhibited the cell survival and invasion, induced cell G0/G1 arrest, and cell apoptosis at the early and late stages. The combined treatment of PARP6 siRNA and survivin siRNA suppressed the cell survival and cell invasion, further induced cell cycle phase G0/G1 arrest, and cell apoptosis at the early and late stages. Taken together, knockdown of PARP6 or survivin promotes cell apoptosis and inhibits the cell invasion of colorectal adenocarcinoma cells. A significant correlation exists between PARP6 and survivin, and both are promising targets for the development of new strategies for the diagnosis and treatment of advanced or metastatic colorectal adenocarcinoma.

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“…Past studies have shown that ectopic expression of SMAD4 induced apoptosis on SiHa cells (Lee et al, 2001), and reduced cervical cancer growth in nude mice (Klein-Scory et al, 2007), indicating a tumor suppressive role for SMAD4 in cervical cancer. Different groups have reported a positive correlation between SMAD4 expression and sensitivity towards cetuximab in head and neck squamous cell carcinoma (Cheng et al, 2015) as well as 5-fluorouracil in breast (Yu et al, 2013) and colorectal cancer (Papageorgis et al, 2011; Zhang et al, 2014; 2016). In this study, we showed that overexpression of SMAD4 in cervical cancer cells augmented anti-proliferative and apoptosis-inducing effects of ACA, indicating that SMAD4 plays a role in regulating response towards anti-cancer agents.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of MicroRNA-210 Confers Sensitivity towards 1’S-1’-Acetoxychavicol Acetate (ACA) in Cervical Cancer Cells by Targeting SMAD4

Phuah¹,

Azmi²,

Awang³

et al. 2017

Molecules and Cells

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MicroRNAs (miRNAs) are short non-coding RNAs that regulate genes posttranscriptionally. Past studies have reported that miR-210 is up-regulated in many cancers including cervical cancer, and plays a pleiotropic role in carcinogenesis. However, its role in regulating response towards anti-cancer agents has not been fully elucidated. We have previously reported that the natural compound 1’S-1’-acetoxychavicol acetate (ACA) is able to induce cytotoxicity in various cancer cells including cervical cancer cells. Hence, this study aims to investigate the mechanistic role of miR-210 in regulating response towards ACA in cervical cancer cells. In the present study, we found that ACA down-regulated miR-210 expression in cervical cancer cells, and suppression of miR-210 expression enhanced sensitivity towards ACA by inhibiting cell proliferation and promoting apoptosis. Western blot analysis showed increased expression of mothers against decapentaplegic homolog 4 (SMAD4), which was predicted as a target of miR-210 by target prediction programs, following treatment with ACA. Luciferase reporter assay confirmed that miR-210 binds to sequences in 3′UTR of SMAD4. Furthermore, decreased in SMAD4 protein expression was observed when miR-210 was overexpressed. Conversely, SMAD4 protein expression increased when miR-210 expression was suppressed. Lastly, we demonstrated that overexpression of SMAD4 augmented the anti-proliferative and apoptosis-inducing effects of ACA. Taken together, our results demonstrated that down-regulation of miR-210 conferred sensitivity towards ACA in cervical cancer cells by targeting SMAD4. These findings suggest that combination of miRNAs and natural compounds could provide new strategies in treating cervical cancer.

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Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade

Cited by 28 publications

References 34 publications

18 β-glycyrrhetinic acid exhibits potent antitumor effects against colorectal cancer via inhibition of cell proliferation and migration

18 β-glycyrrhetinic acid exhibits potent antitumor effects against colorectal cancer via inhibition of cell proliferation and migration

Knockdown of PARP6 or survivin promotes cell apoptosis and inhibits cell invasion of colorectal adenocarcinoma cells

Down-Regulation of MicroRNA-210 Confers Sensitivity towards 1’S-1’-Acetoxychavicol Acetate (ACA) in Cervical Cancer Cells by Targeting SMAD4

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