TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling

Roberts, Cai M.; Tran, Michelle; Pitruzzello, Mary; Wen, Wei; Loeza, Joana; Dellinger, Thanh H.; Mor, Gil; Glackin, Carlotta A.

doi:10.1038/srep37652

Cited by 68 publications

(65 citation statements)

References 61 publications

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“…Collectively, these data demonstrated that TW‐dependent growth of U87MG cells in vivo was associated with activation of AKT. In other cancers, TW regulates AKT signaling through phospho‐activation (Li and Zhou, ) (Roberts et al ., ) as well as transcriptional upregulation (Cheng et al ., ). Here, TW deletion did not alter AKT gene expression (not shown), and therefore, in U87MG TW appears to primarily regulate AKT signaling through phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

et al. 2018

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TWIST1 (TW) is a bHLH transcription factor (TF) and master regulator of the epithelial‐to‐mesenchymal transition (EMT). In vitro, TW promotes mesenchymal change, invasion, and self‐renewal in glioblastoma (GBM) cells. However, the potential therapeutic relevance of TW has not been established through loss‐of‐function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knockdown) on inhibition of tumorigenicity of U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq and the analysis of tumors investigated putative TW‐associated mechanisms. Multiple bioinformatic tools revealed significant alteration of ECM, membrane receptors, signaling transduction kinases, and cytoskeleton dynamics leading to identification of PI3K/AKT signaling. We experimentally show alteration of AKT activity and periostin (POSTN) expression in vivo and/or in vitro. For the first time, we show that effect of TW knockout inhibits AKT activity in U87MG cells in vivo independent of PTEN mutation. The clinical relevance of TW and candidate mechanisms was established by analysis of the TCGA and ENCODE databases. TW expression was associated with decreased patient survival and LASSO regression analysis identified POSTN as one of top targets of TW in human GBM. While we previously demonstrated the role of TW in promoting EMT and invasion of glioma cells, these studies provide direct experimental evidence supporting protumorigenic role of TW independent of invasion in vivo and the therapeutic relevance of targeting TW in human GBM. Further, the role of TW driving POSTN expression and AKT signaling suggests actionable targets, which could be leveraged to mitigate the oncogenic effects of TW in GBM.

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Section: Resultsmentioning

confidence: 99%

Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

et al. 2018

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“…Previous studies have demonstrated that the Gas6/Axl is involved in chemoresistance in breast cancer and indicated that the inactivation of the Gas6/Axl pathway may contribute to the activity of chemotherapeutic drugs (35,36). Recent studies have demonstrated that the inhibition of the Gas6/Axl pathway improved the efficacy of chemotherapies in preclinical models of advanced pancreatic and ovarian cancer (37).…”

Section: Discussionmentioning

confidence: 99%

Luteolin inhibits angiogenesis by blocking Gas6/Axl signaling pathway

Chen

Lei

et al. 2017

International Journal of Oncology

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Growth arrest-specific protein 6 (Gas6) induces the activation of Axl receptor tyrosine kinase (Axl), which plays an important role in angiogenic processes, including proliferation, migration, invasion, tube formation and pericyte recruitment of endothelial cells. The inhibition of Gas6/Axl pathway has been demonstrated to be an effective anti-angiogenic therapy. Luteolin, which is a natural active flavonoid, has been reported to possess anti-angiogenic effects. However, the underlying mechanism of luteolin in anti-angiogenesis is not fully understood. Herein, we report that luteolin significantly inhibited the Gas6-induced proliferation, migration, invasion and tube formation of human microvascular endothelial cells (HMEC‑1s) in vitro, and suppressed the Gas6-induced recruitment of human brain vascular pericytes (HBVPs) to the endothelial tubes. Luteolin also suppressed Gas6-induced microvessel sprouting in aortic ring assay and neovascularization in chick chorioallantoic membrane assay. The anti-angiogenic effect of luteolin may be associated with the inhibition of the Gas6/Axl pathway and its downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Taken together, the present study provides new evidence regarding an anti-angiogenic mechanism of luteolin, and supports the notion that the dietary intake of luteolin contributes to the treatment of pathological angiogenesis.

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“…RNA sequencing analysis revealed that TWIST1 expression resulted in upregulation of GAS6 and the activation of the AKT pathway. On the other side, knockdown studies demonstrated that the loss of GAS6 sensitized these cells to cisplatin treatment and suggest a potential mechanism of drug resistance in EOC (Roberts et al, 2016). Lee et al could show that GAS6 regulates the cell cycle and apoptosis of prostate cancer (PCa) cells in response to docetaxel chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

GAS6‐expressing and self‐sustaining cancer cells in 3D spheroids activate the PDK‐RSK‐mTOR pathway for survival and drug resistance

2017

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AXL receptor tyrosine kinase (RTK) inhibition presents a promising therapeutic strategy for aggressive tumor subtypes, as AXL signaling is upregulated in many cancers resistant to first‐line treatments. Furthermore, the AXL ligand growth arrest‐specific gene 6 (GAS6) has recently been linked to cancer drug resistance. Here, we established that challenging conditions, such as serum deprivation, divide AXL‐overexpressing tumor cell lines into non‐self‐sustaining and self‐sustaining subtypes in 3D spheroid culture. Self‐sustaining cells are characterized by excessive GAS6 secretion and TAM‐PDK‐RSK‐mTOR pathway activation. In 3D spheroid culture, the activation of the TAM‐PDK‐RSK‐mTOR pathway proves crucial following treatment with AXL/MET inhibitor BMS777607, when the self‐sustaining tumor cells react with TAM‐RSK hyperactivation and enhanced SRC‐AKT‐mTOR signaling. Thus, bidirectional activated mTOR leads to enhanced proliferation and counteracts the drug effect. mTOR activation is accompanied by an enhanced AXL expression and hyperphosphorylation following 24 h of treatment with BMS777607. Therefore, we elucidate a double role of AXL that can be assigned to RSK‐mTOR as well as SRC‐AKT‐mTOR pathway activation, specifically through AXL Y779 phosphorylation. This phosphosite fuels the resistance mechanism in 3D spheroids, alongside further SRC‐dependent EGFR Y1173 and/or MET Y1349 phosphorylation which is defined by the cell‐specific addiction. In conclusion, self‐sustenance in cancer cells is based on a signaling synergy, individually balanced between GAS6 TAM‐dependent PDK‐RSK‐mTOR survival pathway and the AXLY779/EGFR/MET‐driven SRC‐mTOR pathway.

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TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling

Cited by 68 publications

References 61 publications

Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma

Luteolin inhibits angiogenesis by blocking Gas6/Axl signaling pathway

GAS6‐expressing and self‐sustaining cancer cells in 3D spheroids activate the PDK‐RSK‐mTOR pathway for survival and drug resistance

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