Twist promotes reprogramming of glucose metabolism in breast cancer cells through PI3K/AKT and p53 signaling pathways

Yang, Li; Hou, Yixuan; Yuan, Jie; Tang, Shifu; Zhang, Hailong; Zhu, Qing; Du, Yan‐e; Zhou, Maosheng; Wen, Siyang; Xu, Lixiang; Tang, Xi; Cui, Xiaojiang; Liu, Manran

doi:10.18632/oncotarget.4697

Cited by 97 publications

(75 citation statements)

References 53 publications

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“…Hence, Twist is an important stimulating factor in the process of EMT. Some previous studies have shown that the activation of the PI3K/AKT signaling pathway lead to a high level of Twist expression [22,23]. In the present study, we found that Huaier could reverse the EMT in 786-O cells and reduce Twist expression.…”

Section: Discussionsupporting

confidence: 67%

The Anticancer Effect of Huaier Extract in Renal Cancer 786-O Cells

Wei

Liu

et al. 2018

Pharmacology

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Background: Trametes robiniophila Murr (Huaier) has been used as an adjuvant therapy of tumor in traditional Chinese medicine for many years, but the underlying mechanisms are largely unknown. In the present study, we tested the inhibitory effect of Huaier extract on renal cancer 786-O cells and explored the possible mechanisms. Methods: 786-O cells were treated by gradient concentrations of Huaier extract, cell viability, invasion, migration and apoptosis were assessed by cell counting kit 8, cell scratch, transwell, and flow cytometry assay in vitro. The changes in protein level were detected by western blot analysis. Finally, the anticancer effect of Huaier was tested in vivo by nude mouse tumorigenicity assay. Results: Viability of 786-O cells was suppressed by Huaier in a time- and dose-dependent manner; cell invasion and migration were also dramatically inhibited. Flow cytometry assays showed that Huaier could induce cell apoptosis. Western blotting analysis indicated that Huaier suppressed the activation of PI3K/AKT/mTOR/p70S6K/4E-BP1 signaling pathway. We also found that Huaier could partly reverse the epithelialmesenchymal transition (EMT) process. In vivo experiment indicated that tumor growth in the xenograft mouse model was suppressed by Huaier. Conclusion: Huaier plays an anticancer effect partially through the suppression of the PI3K/AKT/mTOR/p70S6K/4E-BP1 pathway and by reversing the EMT process. Huaier may act as an effective agent for treating renal cell carcinoma.

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Section: Discussionsupporting

confidence: 67%

The Anticancer Effect of Huaier Extract in Renal Cancer 786-O Cells

Wei

Liu

et al. 2018

Pharmacology

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“…This fact has repeatedly been confirmed in more recent studies [8–14] indicating that G6PD plays an important role in the metabolism of cancer cells.…”

Section: Supportive Evidencesupporting

confidence: 65%

Simultaneous dual targeting of Par-4 and G6PD: a promising new approach in cancer therapy? Quintessence of a literature review on survival requirements of tumor cells

Cernaj¹

2016

Cancer Cell Int

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The aim of this hypothesis is to propose a new approach in targeted therapy of cancer: The simultaneous, dual targeting of two single molecules, Par-4 and G6PD, rather than inhibition of full-length signaling pathways. Rationale: Targeted inhibition of especially two survival signaling pathways (PI3K/AKT/mTOR and MAPK/ERK) is frequently tried, however, a major breakthrough has not yet been reported. Inhibition of complete pathways naturally goes along with a variety of dose-limiting side effects thus contributing to poor efficacy of the administered drugs. This essay offers a synopsis of relevant studies to support the above mentioned idea—targeting of two single molecules which either are crucial for tumor growth and cancer-cell-survival: on one side, Par-4-activation selectively triggers apoptosis of tumor cells thus reversing their characteristic feature—immortality. On the other side inhibition of G6PD breaks the energy supply of tumor cells, weakens their defence against oxidative stress and thereby enhances the sensitivity of tumor cells to oxidative agents (e.g. chemotherapy). Advantage of the proposed dual Par-4/G6PD-therapy is good tolerability and—especially when administered along with conventional therapy—less frequent emergence of resistance.

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“…For treatment of Ku60019 (S1570, Selleck Chemicals), an specific oxidized ATM inhibitor, cells were grown to approximately 60% confluence, the culture medium was replaced by fresh medium containing 1 µM, 3µM, 5µM Ku60019 or vehicle for 6 hours. The transfections of the indicated plasmids into cells were performed as described previously [29].…”

Section: Cell Culture Treatments and Transfectionsmentioning

confidence: 99%

ATM-Mediated Phosphorylation of Cortactin Involved in Actin Polymerization Promotes Breast Cancer Cells Migration and Invasion

Lei

Hou

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: The ataxia-telangiectasia mutated (ATM) protein kinase is critical for the maintenance of genomic stability and acts as tumor suppressor. Although evidence shows that a DNA damage-independent ATM (oxidized ATM) may be involved in cancer progression, the underlying mechanism is still unclear. Methods: Immunohistochemistry, immunofluorescence and western blotting were applied to detect the levels of oxidized ATM. Transwell assay was used to detect the cell migration and invasion abilities in different treatments. Quantitative phosphoproteome analysis was performed using hypoxic BT549 cells, in the presence or absence of Ku60019, a specific inhibitor of ATM kinase. The phosphorylated cortactin, the target protein of oxidized ATM, was confirmed by immunoprecipitation-western blots and in vitro kinase assay. The functions of phosphorylated cortactin were studied by specific short hairpin RNA, site-directed mutation, transwell assay, and actin polymerization assay. Results: Enhanced oxidized ATM proteins were present not only in the advanced and invasive breast tumor tissues but also malignant hypoxic breast cancer cells, in the absence of DNA damage. Loss of ATM expression or inhibiting oxidized ATM kinase activity reduced breast cancer cell migration and invasion. Using quantitative phosphoproteomics approach, 333 oxidized ATM target proteins were identified, some of these proteins govern key signaling associated with gap junction, focal adhesion, actin cytoskeleton rearrangement. Cortactin, one of the biggest changed phospho-protein, is a novel oxidized ATM-dependent target in response to hypoxia. Mechanically, we reveal that hypoxia-activated ATM can enhance the binding affinity of cortactin with Arp2/3 complex by phosphorylating cortactin at serine 113, and as a result, in favor of breast cancer cell migration and invasion. Conclusion: Oxidized ATM can phosphorylate cortactin at serine 113, playing a critical role in promoting breast tumor cell mobility and invasion via actin polymerization.

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Twist promotes reprogramming of glucose metabolism in breast cancer cells through PI3K/AKT and p53 signaling pathways

Cited by 97 publications

References 53 publications

The Anticancer Effect of Huaier Extract in Renal Cancer 786-O Cells

The Anticancer Effect of Huaier Extract in Renal Cancer 786-O Cells

Simultaneous dual targeting of Par-4 and G6PD: a promising new approach in cancer therapy? Quintessence of a literature review on survival requirements of tumor cells

ATM-Mediated Phosphorylation of Cortactin Involved in Actin Polymerization Promotes Breast Cancer Cells Migration and Invasion

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