Resveratrol Inhibition of Renal Cancer Stem Cell Characteristics and Modulation of the Sonic Hedgehog Pathway

Sun, Hongzan; Zhang, Taotao; Li, Rui; Cao, Wanshuang; Zhang, Zhiqiang; Liu, Zhiqi; Qian, Weiwei; Wang, Dengdian; Yu, Dexin; Zhong, Caiyun

doi:10.1080/01635581.2020.1784966

Cited by 13 publications

(6 citation statements)

References 46 publications

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“…Besides BMI-1, RV also downregulated the expression of GLI1, SNAIL-1 and TWIST1. These findings are in agreement with other reports proving the inhibitory activity of RV on the Hedgehog-GLI pathway in different cancers, supporting its adjuvant therapeutic potential to treat cancers with hyper-active Hedgehog signaling [52][53][54][55][56][57].…”

Section: Discussionsupporting

confidence: 93%

Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

Ferraresi

Esposito

Girone

et al. 2021

Cells

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Background: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. Aims: To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. Results: LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. BMI-1 silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In in vitro 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. Conclusions: By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance.

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Section: Discussionsupporting

confidence: 93%

Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

Ferraresi

Esposito

Girone

et al. 2021

Cells

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“…It was demonstrated that RES inhibited the malignant characteristics of pancreatic cancer cells [36] and renal cancer stem cells [37] by blocking Hedgehog signaling pathway. Our results had showed that RES significantly downregulated the expression levels of SMO, Gli1, and Shh in the Hedgehog signaling pathway of HeLa cells.…”

Section: Biomed Research Internationalmentioning

confidence: 99%

Resveratrol Induces Apoptosis, Suppresses Migration, and Invasion of Cervical Cancer Cells by Inhibiting the Hedgehog Signaling Pathway

Jiang

Liu

Zhou

et al. 2022

BioMed Research International

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To investigate the effect and mechanism of resveratrol on the biological behavior of cervical cancer cells (HeLa cells), the apoptosis, migration, and invasion of HeLa cells were detected by flow cytometry, wound healing, and transwell assays. The expression levels of Hedgehog signal pathway proteins (smoothened (SMO), zinc finger transcription factors (Gli1), and sonic hedgehog homolog (Shh)) were detected by quantitative real-time PCR (qPCR) and western blotting. Compared with that control group, resveratrol (RES) significantly induced apoptosis, inhibited the migration and invasion of the HeLa cells. The expression of SMO, Gli1, and Shh were downregulated in the HeLa cells treated with RES. The Hedgehog agonist purmorphamine (PUR) reversed the RES-induced increase of apoptosis and reduction of migration and invasion in the HeLa cells. In conclusion, RES induced the apoptosis and suppressed the migration and invasion of HeLa cells by inhibiting Hedgehog signal pathway.

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“…The tumor sphere formation capacity in renal cancer is mediated by CSCs and Sonic signaling plays a significant role in this case. The Res administration (0–30 μM) down-regulates Sonic signaling to inhibit CSCs features in renal cancer, leading to apoptosis and proliferation inhibition [ 348 ]. As it was mentioned earlier, Res is loaded on nanoparticles to promote its anti-tumor activity [ 349 , 350 , 351 ].…”

Section: Dietary Agents and Cancer Stem Cellsmentioning

confidence: 99%

Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies

Paskeh

Asadi²,

Zabolian

et al. 2021

IJMS

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As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use.

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Resveratrol Inhibition of Renal Cancer Stem Cell Characteristics and Modulation of the Sonic Hedgehog Pathway

Cited by 13 publications

References 46 publications

Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

Resveratrol Induces Apoptosis, Suppresses Migration, and Invasion of Cervical Cancer Cells by Inhibiting the Hedgehog Signaling Pathway

Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies

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