Knockdown of HIF-1α by siRNA-expressing plasmid delivered by attenuated Salmonella enhances the antitumor effects of cisplatin on prostate cancer

Gu, Junlian; Li, Yang; Zeng, Jun; Wang, Bo; Ji, Kun; Tang, Yufeng; Sun, Qing

doi:10.1038/s41598-017-07973-4

Cited by 38 publications

(27 citation statements)

References 44 publications

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“…et al, 2012). In addition, in prostate xenografts, the effective downregulation of Hif-1α using salmonella to deliver shRNA-expressing plasmids resulted in increased sensitivity to cisplatin (CDDP) (Gu et al, 2017). However, for the improved drug distribution and response after either TGFβ-or Hif-1α targeting, alternative mechanisms cannot be excluded: TGFβ does not only induce increased ECM build-up and stabilization, but it is also an important regulator of tumor angiogenesis (reviewed in Goumans et al, 2009;van Meeteren et al, 2011).…”

Section: Targeting Tgfβ and Hif1αmentioning

confidence: 99%

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Henke

Nandigama

Ergün

2020

Front. Mol. Biosci.

721

613

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Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

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Section: Targeting Tgfβ and Hif1αmentioning

confidence: 99%

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Henke

Nandigama

Ergün

2020

Front. Mol. Biosci.

721

613

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“…Several studies have showed that ELK3 is overexpressed in some cancer cells and correlates with cell migration and invasion [13][14][15]. Hypoxiainducible factor-1α (HIF-1α) can regulate the genes related to cell proliferation, apoptosis, angiogenesis, and metastasis, playing an important role in cancer progression [16][17][18]. Lee et al found that ELK3 expression was upregulated in CD133 + /CD44 + liver cancer stem cells, and silencing of ELK3 attenuated their metastatic potential by regulating HIF-1α expression [12].…”

Section: Introductionmentioning

confidence: 99%

Silencing of ELK3 Induces S-M Phase Arrest and Apoptosis and Upregulates SERPINE1 Expression Reducing Migration in Prostate Cancer Cells

Mao

Bao

et al. 2020

BioMed Research International

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ELK3, an ETS domain-containing transcription factor, participates in various physiological and pathological processes including cell proliferation, migration, angiogenesis, and malignant progression. However, the role of ELK3 in prostate cancer cells and its mechanism are not fully understood. The contribution of ELK3 to prostate cancer progression was investigated in the present study. We showed that silencing of ELK3 by siRNA in prostate cancer cell DU145 induced S-M phase arrest, promoted apoptosis, inhibited cell proliferation and migration in vitro, and suppressed xenograft growth in mice in vivo. In accordance with its ability to arrest cells in S-M phase, the expression of cyclin A and cyclin B was downregulated. In addition, the expression of p53 was upregulated following ELK3 knockdown, while that of antiapoptotic Bcl-2 was decreased. The migration inhibition may partly due to upregulation of SERPINE1 (a serine protease inhibitor) followed ELK3 knockdown. Consistently, downregulation of SERPINE1 resulted in a modest elimination of migration inhibition resulted from ELK3 knockdown. Furthermore, we found that the AKT signaling was activated in ELK3 knockdown cells, and treatment these cells with AKT inhibitor attenuated SERPINE1 expression induced by ELK3 silencing, suggesting that activation of AKT pathway may be one of the reasons for upregulation of SERPINE1 after ELK3 knockdown. In conclusion, modulation of ELK3 expression may control the progression of prostate cancer partly by regulating cell growth, apoptosis, and migration.

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“…Accordingly, hypoxia-mediated chemoresistance has been regarded as an important obstacle in the development of cancer treatment [ 11 ]. Hypoxia inducible factor-1α (HIF-1α) is an important regulator of transcription in response to hypoxia, which activates the expression of more than 60 target genes involved in cell proliferation, apoptosis, and glycolysis [ 12 ]. It is believed that HIF-1α-induced glycolysis plays a critical role in promoting chemoresistance of NSCLC cells [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of KLF5 suppresses hypoxia-induced resistance to cisplatin in NSCLC cells by regulating HIF-1α-dependent glycolysis through inactivation of the PI3K/Akt/mTOR pathway

et al. 2018

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BackgroundHypoxia-mediated chemoresistance has been regarded as an important obstacle in the development of cancer treatment. Knockdown of krüppel-like factor 5 (KLF5) was reported to inhibit hypoxia-induced cell survival and promote cell apoptosis in non-small cell lung cancer (NSCLC) cells via direct regulation of hypoxia inducible factor-1α (HIF-1α) expression. However, the roles of KLF5 in the development of hypoxia-induced cisplatin (DDP) resistance and its underlying mechanism in NSCLC cells remain to be further elucidated.MethodsWestern blot was performed to determine the protein levels of KLF5, P-glycoprotein (P-gp) and HIF-1α in treated NSCLC cells. Cell survival was examined by MTT assay. The effect of KLF5 knockdown on hypoxia-induced glycolysis was assessed by measuring glucose consumption and lactate production. The effect of KLF5 knockdown on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway was analyzed by western blot.ResultsHypoxia upregulated the expression of KLF5 in NSCLC cells. KLF5 knockdown suppressed hypoxia-induced DDP resistance in NSCLC cells, as demonstrated by the increased cytotoxic effects of DDP and reduced P-gp expression in NSCLC cells in hypoxia. Moreover, KLF5 knockdown inhibited hypoxia-induced HIF-1α expression and glycolysis, and KLF5 knockdown suppressed hypoxia-induced DDP resistance by inhibiting HIF-1α-dependent glycolysis in NSCLC cells. Furthermore, KLF5 knockdown suppressed hypoxia-induced activation of the PI3K/Akt/mTOR pathway in NSCLC cells and KLF5 overexpression promoted hypoxia-induced DDP resistance in NSCLC cells through activation of the PI3K/Akt/mTOR pathway.ConclusionsKLF5 knockdown could suppress hypoxia-induced DDP resistance, and its mechanism may be due to the inhibition of HIF-1α-dependent glycolysis via inactivation of the PI3K/Akt/mTOR pathway.

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Knockdown of HIF-1α by siRNA-expressing plasmid delivered by attenuated Salmonella enhances the antitumor effects of cisplatin on prostate cancer

Cited by 38 publications

References 44 publications

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Silencing of ELK3 Induces S-M Phase Arrest and Apoptosis and Upregulates SERPINE1 Expression Reducing Migration in Prostate Cancer Cells

Knockdown of KLF5 suppresses hypoxia-induced resistance to cisplatin in NSCLC cells by regulating HIF-1α-dependent glycolysis through inactivation of the PI3K/Akt/mTOR pathway

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