Inhibition of the STAT3 signaling pathway contributes to apigenin-mediated anti-metastatic effect in melanoma

Cao, Hongxin; Chu, Jian-Hong; Kwan, Hiu Yee; Su, Tao; Yu, Hua; Cheng, Chi-Yan; Fu, Xiu‐Qiong; Guo, Hui; Li, Ting; Tse, Anfernee Kai-Wing; Chou, Gui‐Xin; Mo, Huanbiao; Yu, Zhi‐Ling

doi:10.1038/srep21731

Cited by 107 publications

(89 citation statements)

References 60 publications

(83 reference statements)

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“…TPP also reduced the growth of ovarian cancer cells in culture48. Furthermore, an inhibitor of STAT3 reduced downstream activity of TWIST1, which led to impeded migration and invasion of melanoma cells49. Our group has also demonstrated the efficacy of TWIST1 siRNA in reducing melanoma growth in vivo via inhibition of apoptosis11.…”

Section: Discussionmentioning

confidence: 70%

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

Roberts

Tran²,

Pitruzzello

et al. 2016

Sci Rep

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Epithelial ovarian cancer (EOC) is the most deadly gynaecologic malignancy due to late onset of symptoms and propensity towards drug resistance. Epithelial-mesenchymal transition (EMT) has been linked to the development of chemoresistance in other cancers, yet little is known regarding its role in EOC. In this study, we sought to determine the role of the transcription factor TWIST1, a master regulator of EMT, on cisplatin resistance in an EOC model. We created two Ovcar8-derived cell lines that differed only in their TWIST1 expression. TWIST1 expression led to increased tumour engraftment in mice, as well as cisplatin resistance in vitro. RNA sequencing analysis revealed that TWIST1 expression resulted in upregulation of GAS6 and L1CAM and downregulation of HMGA2. Knockdown studies of these genes demonstrated that loss of GAS6 or L1CAM sensitized cells to cisplatin, but that loss of HMGA2 did not give rise to chemoresistance. TWIST1, in part via GAS6 and L1CAM, led to higher expression and activation of Akt upon cisplatin treatment, and inhibition of Akt activation sensitized cells to cisplatin. These results suggest TWIST1- and EMT-driven increase in Akt activation, and thus tumour cell proliferation, as a potential mechanism of drug resistance in EOC.

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Section: Discussionmentioning

confidence: 70%

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

Roberts

Tran²,

Pitruzzello

et al. 2016

Sci Rep

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“…STAT-3 inhibition was associated with downregulation of N-cadherin, fibronectin, MMP-2, MMP-9, and Twist1 and upregulation of keratin-8 and E-cadherin. Overexpression of Twist1 restored the invasive and migratory potential of A375 cells treated with apigenin [159]. Additionally, apigenin treatment decreased integrin expression, inhibited the phosphorylation of FAK, and decreased activation of ERK1/2 in A2058 and A375 cells [160].…”

Section: Phytochemicals With Known Anti-emt Propertiesmentioning

confidence: 99%

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

et al. 2017

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Melanoma is a cutaneous neoplastic growth of melanocytes with great potential to invade and metastasize, especially when not treated early and effectively. Epithelial-mesenchymal transition (EMT) is the process by which melanocytes lose their epithelial characteristics and acquire mesenchymal phenotypes. Mesenchymal protein expression increases the motility, invasiveness, and metastatic potential of melanoma. Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, and several others. Downstream effectors of these pathways induce expression of EMT transcription factors including Snail, Slug, Twist, and Zeb that promote repression of epithelial and induction of mesenchymal character. Emerging research has demonstrated that a variety of small molecule inhibitors as well as phytochemicals can influence the progression of EMT and may even reverse the process, inducing re-expression of epithelial markers. Phytochemicals are of particular interest as supplementary treatment options because of their relatively low toxicities and anti-EMT properties. Modulation of EMT signaling pathways using synthetic small molecules and phytochemicals is a potential therapeutic strategy for reducing the aggressive progression of metastatic melanoma. In this review, we discuss the emerging pathways and transcription factor targets that regulate EMT and evaluate potential synthetic small molecules and naturally occurring compounds that may reduce metastatic melanoma progression.

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“…Apigenin effectively inhibited STAT3‐mediated transcriptional regulation of Bcl‐XL and Mcl‐1 to induce apoptosis in colon cancer cells . Apigenin was also noticed to be effective against melanoma as evidenced by reduced constitutive STAT3 phosphorylation, lower levels of STAT3 in nucleus, and consequent STAT3‐luciferase reporter activities in A375 melanoma cells . Interestingly, matrix metalloproteinase‐2 (MMP‐2) and Twist1 were transcriptionally controlled by STAT3 in melanoma cells.…”

Section: Jak‐stat Signalingmentioning

confidence: 99%

Apigenin as an effective anticancer natural product: Spotlight on TRAIL, WNT/β‐catenin, JAK‐STAT pathways, and microRNAs

Özbey

Attar

Romero

et al. 2018

J of Cellular Biochemistry

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Wealth of information gleaned from decades of high‐impact research work; scientists have disentangled the complicated web of versatile regulators that underlie cancer development and progression. Use of structural biology approaches and functional genomics have helped us to gain new insights into complex nature of cancer, and it is now clear that genetic/epigenetic mutations, overexpression of oncogenes, inactivation of tumor suppressors, loss of apoptosis, and versatility of protein binding partners have contributory roles in carcinogenesis and metastatic spread. It is becoming progressively more understandable that reprogramming of gene expression during and nontranscriptional changes during cancer development and progression are initiated and controlled by deregulated signal transduction cascades, all of which collectively create an incalculable complexity. Data obtained through preclinical and clinical trials revealed that alterations in the targeted oncogenes and other downstream, and parallel pathways played a central role in the development of resistance against different therapeutics. Phytochemicals have regained limelight, and different natural products are currently being tested for efficacy in preclinical studies. Apigenin, a plant‐derived flavonoid has considerable pharmacological value and is reportedly involved in the regulation of different signaling cascades. In this review, we have attempted to summarize rapidly evolving understanding of molecular biologists and pharmacologists about the potential of apigenin in the regulation of deregulated signaling pathways in different cancers. We have emphasized on the regulation of WNT/β‐catenin and janus kinase/signal transducers and activators of transcription (JAK‐STAT) pathways. We also comprehensively discuss how apigenin restored apoptosis in tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐resistant cancers. The review also gives a snapshot of microRNAs (miRNAs) that regulate wide‐ranging biological processes, and it is now clear that each miRNA can control hundreds of gene targets. Apigenin was noted to upregulate miR‐520b and miR‐101 in different cancers to inhibit tumor growth. Moreover, apigenin‐induced apoptotic rate was significantly higher when used in combination with miR‐423‐5p inhibitors or miR‐138 mimics. Better comprehension of linear and integrated signaling pathways will be helpful in effective therapeutic targeting of deregulated signaling pathways to inhibit/prevent cancer.

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Inhibition of the STAT3 signaling pathway contributes to apigenin-mediated anti-metastatic effect in melanoma

Cited by 107 publications

References 60 publications

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

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

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

Apigenin as an effective anticancer natural product: Spotlight on TRAIL, WNT/β‐catenin, JAK‐STAT pathways, and microRNAs

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