Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil

Ishida, Kazunari; Ito, Chie; Ohmori, Yukimi; Kume, Kohei; Sato, Kei; Koizumi, Yuka; Konta, Akari; Iwaya, Takeshi; Nukatsuka, Mamoru; Kobunai, Takashi; Takechi, Teiji; Nishizuka, Satoshi

doi:10.1038/s41598-017-02548-9

Cited by 9 publications

(10 citation statements)

References 53 publications

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“…The protein expression pattern of 5FU treatment in the present study was similar to that of EGCG treatment, which was consistent with a previous study showing that the changes caused by 5FU injection in an orthotopic xenograft of human gastric cancer cells in the gastric submucosal layer from nude mice on the protein expression of the PI3K/Akt/mTOR pathway were small [122]. Furthermore, our results suggested that EGCG could be used as anticancer agent without creating undesirable side effects for healthy organs of the tumor-bearing host.…”

Section: Discussionsupporting

confidence: 92%

Epigallocatechin gallate triggers apoptosis by suppressing de novo lipogenesis in colorectal carcinoma cells

et al. 2022

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The de novo lipogenesis (DNL) pathway has been identified as a regulator of cancer progression and aggressiveness. Downregulation of key lipogenesis enzymes has been shown to activate apoptosis in cancerous cells. Epigallocatechin gallate (EGCG) inhibits cancer cell proliferation without causing cytotoxicity in healthy cells. The present study aimed to investigate the effects of EGCG on the promotion of apoptosis associated with the DNL pathway inhibition in cancer cells, both in vitro and in vivo. We observed that two colorectal cancer cell lines (HCT116 and HT‐29) had a higher cytotoxic response to EGCG treatment than hepatocellular carcinoma cells, including HepG2 and HuH‐7. EGCG treatment decreased cell viability and increased mitochondrial damage‐triggered apoptosis in both HCT116 and HT‐29 cancer cells. Additionally, we treated mice transplanted with HCT116 cells with 30 or 50 mg·kg−1 EGCG for 7 days to evaluate the apoptotic effects of EGCG treatment in a xenograft mouse model of cancer. We observed a decrease in intracellular fatty acid levels, which suggested that EGCG‐induced apoptosis was associated with a decrease in fatty acid levels in cancer. Suppression of ATP synthesis by EGCG indicated that cell death induction in cancer cells could be mediated by shared components of the DNL and energy metabolism pathways. In addition, EGCG‐induced apoptosis suppressed the expression of the phosphorylation protein kinase B and extracellular signal‐regulated kinase 1/2 signaling proteins in tumors from xenografted mice. Cytotoxic effects in unaffected organs and tissues of the mouse xenograft model were absent upon EGCG treatment.

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Section: Discussionsupporting

confidence: 92%

Epigallocatechin gallate triggers apoptosis by suppressing de novo lipogenesis in colorectal carcinoma cells

et al. 2022

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“…it is widely accepted that the Pi3K/akt pathway plays an important role in drug resistance. overexpression of this Pi3K/akt pathway has been identified in 5-Fu-resistant cell lines, and the blocking of this pathway could sensitize cancer cells to 5-Fu in vitro (37). However, activation of the Pi3K/akt pathway was revealed to induce 5-Fu resistance in cancer cells (38).…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway

Wei

Lin

et al. 2019

Mol Med Report

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combination chemotherapy with chemosensitizers can exert synergistic therapeutic effects, reduce toxicity, and delay the induction of drug resistance. in the present study, the antitumor effects were investigated, and the possible underlying mechanisms of kaempferol combined with 5-fluorouracil (5-Fu) in colorectal cancer cells were explored. HcT-8 or HcT-116 cells were treated with various concentrations of kaempferol and/or 5-Fu for the indicated time-points. an MTT assay was used to determine cell viability, whereas the synergistic effects were assessed by calculating the combination indices of kaempferol and 5-Fu. annexin V analysis and Hoechst staining were used to determine cell apoptosis. q-Pcr and western blotting were performed to determine the expression levels of Bax, Bcl-2, thymidylate synthase (TS), PTen, Pi3K, aKT, and p-aKT. The combination of kaempferol and 5-Fu was determined to be more effective in inhibiting cell viability than either of the agents alone. The inhibition of tumors in response to kaempferol and 5-Fu was associated with the reduction in proliferation ability and stimulation of apoptosis. The protein results indicated that kaempferol and 5-FU could significantly upregulate the expression levels of Bax and downregulate the expression levels of Bcl-2 and TS. Furthermore, the combination treatment greatly inhibited the activation of the Pi3K/akt pathway, suggesting the involvement of this pathway in the synergistic effects. The present study demonstrated that kaempferol has a synergistic effect with 5-Fu by inhibiting cell proliferation and inducing apoptosis in colorectal cancer cells via suppression of TS or attenuation of p-akt activation. The combination of kaempferol and 5-Fu may be used as an effective therapeutic strategy for colorectal cancer.

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“…Activation of the PI3K-AKT pathway is among the most important mechanisms of enhanced chemoresistance in gastric cancer [ 27 , 28 ]. Inhibition of PI3K can suppress propagation of drug-tolerant gastric cancer cell subpopulations enriched by 5-fluorouracil [ 29 ] and also strengthen their response to multiple chemotherapeutic reagents [ 30 , 31 ]. GLI1- mediated activation of PI3K/AKT pathway was observed in colorectal cancer [ 32 ], ovarian cancer [ 33 ], and hepatocellular carcinoma [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis of GLI1 and Related Signaling Pathways in Chemosensitivity of Gastric Cancer

Jia

et al. 2018

Med Sci Monit

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BackgroundThis study assessed the prognostic value of GLI1 in gastric cancer and analyzed the possible GLI1-related signaling network in chemosensitivity.Material/MethodsBioinformatic data mining was performed by using data in the TCGA-Stomach Cancer (TCGA-STAD) and the Kaplan-Meier plotter. GLI1 co-expressed genes in TCGA-STAD were subjected to KEGG pathway analysis. The genes enriched in the KEGG pathways were further subjected to Protein-Protein Interaction (PPI) analysis.ResultsIn TCGA-STAD, high GLI1 gene/exon expression was associated with significantly worse survival (p=0.016 and 0.0023 respectively). In the Kaplan-Meier plotter, high GLI1 expression was associated with unfavorable overall survival (OS) (HR: 1.68, 95%CI: 1.42–2, p<0.0001) and first progression-free survival (FPS) (HR: 1.72, 95%CI: 1.4–2.11, p<0.0001). In TCGA-STAD, 600 GLI1 co-expressed genes were identified (absolute Pearson’s r ≥0.5). The most significant pathways were pathways in cancer (p=230.0E-12) and the Hedgehog signaling pathway (p=6.9E-9). PI3K-AKT pathway (p=17.0E-9) has the largest proportion of gene enrichment. Some GLI1 co-expressed genes in the PI3K-AKT pathway are central nodes in the PPI network and also play important roles in chemosensitivity of gastric cancer. Nevertheless, the mechanisms underlying their co-expression are still largely unexplored.ConclusionsHigh GLI1 expression is associated with unfavorable OS and FPS in patients with gastric cancer. As a member of the Hedgehog signaling pathway, GLI1 co-expressed genes are also largely enriched in PI3K/AKT pathway in gastric cancer, which is closely related to chemoresistance. The underlying mechanisms are still largely unexplored and need further study.

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Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil

Cited by 9 publications

References 53 publications

Epigallocatechin gallate triggers apoptosis by suppressing de novo lipogenesis in colorectal carcinoma cells

Epigallocatechin gallate triggers apoptosis by suppressing de novo lipogenesis in colorectal carcinoma cells

Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway

Bioinformatic Analysis of GLI1 and Related Signaling Pathways in Chemosensitivity of Gastric Cancer

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