Targeting NF-κB and HIF-1 Pathways for the Treatment of Cancer: Part II

Wilczyński, Jacek R.; Duechler, Markus; Czyż, Małgorzata

doi:10.1007/s00005-011-0132-3

Cited by 29 publications

(9 citation statements)

References 70 publications

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“…Until recently TIMP-1 and HIF-1α (and in consequence miR-210) were seemingly totally un-related factors whose elevation is associated with bad prognosis for cancer patients (Zucker et al, 2000; Chan and Loscalzo, 2010; Wilczynski et al, 2011). In this review, we propose a functional pro-metastatic co-operation of these factors that link microenvironmental conditions to stress response involving the emerging field of gene regulation by miRNAs.…”

Section: Resultsmentioning

confidence: 99%

“…HIF-1 can also be induced by hypoxia-independent factors (Wenger et al, 2005), such as inflammatory cytokines like IFN-γ and IL-4 (Majmundar et al, 2010) as well as NF-κB (Wilczynski et al, 2011). HIF-1α mRNA expression and protein stability are further upregulated by mTORC1 (Bernardi et al, 2006) and the PI3K pathway (Mottet et al, 2003), which can initiate a HIF-1-mediated response independent of hypoxic stress.…”

Section: Hif-1α Regulates Response Of Tumor Cells To Stressmentioning

confidence: 99%

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On the Pro-Metastatic Stress Response to Cancer Therapies: Evidence for a Positive Co-Operation between TIMP-1, HIF-1α, and miR-210

Cui¹,

Grosso²,

Schelter³

et al. 2012

Front. Pharmacol.

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In contrast to expectations in the past that tumor starvation or unselective inhibition of proteolytic activity would cure cancer, there is accumulating evidence that microenvironmental stress, such as hypoxia or broad-spectrum inhibition of metalloproteinases can promote metastasis. In fact, malignant tumor cells, due to their genetic and epigenetic instability, are predisposed to react to stress by adaptation and, if the stress persists, by escape and formation of metastasis. Recent recognition of the concepts of dynamic evolution as well as population and systems biology is extremely helpful to understand the disappointments of clinical trials with new drugs and may lead to paradigm-shifts in therapy strategies. This must be complemented by an increased understanding of molecular mechanism involved in stress response. Here, we review new roles of Hypoxia-inducible factor-1 (HIF-1), one transcription factor regulating stress response-related gene expression: HIF-1 is crucial for invasion and metastasis, independent from its pro-survival function. In addition, HIF-1 mediates pro-metastatic microenvironmental changes of the proteolytic balance as triggered by high systemic levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), typical for many aggressive cancers, and regulates the metabolic switch to glycolysis, notably via activation of the microRNA miR-210. There is preliminary evidence that TIMP-1 also induces miR-210. Such positive-regulatory co-operation of HIF-1α, miR-210, and TIMP-1, all described to correlate with bad prognosis of cancer patients, opens new perspectives of gaining insight into molecular mechanisms of metastasis-inducing evasion of tumor cells from stress.

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Section: Resultsmentioning

confidence: 99%

Section: Hif-1α Regulates Response Of Tumor Cells To Stressmentioning

confidence: 99%

On the Pro-Metastatic Stress Response to Cancer Therapies: Evidence for a Positive Co-Operation between TIMP-1, HIF-1α, and miR-210

Cui¹,

Grosso²,

Schelter³

et al. 2012

Front. Pharmacol.

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“…6 HIF-1 α can induce the expression of multiple target genes such as VEGF 29 (an important angiogenesis factor), CXCR4 30 (an important factor regulating cell migration), adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) 31 (a pro-cell death member of the Bcl-2 family) and CAIX 31 (a marker for hypoxia). Thus, HIF-1 α can activate downstream pathways involved in proliferation, metabolism, differentiation and angiogenesis, 32, 33 which likely account for the ability of HIF-1 α to keep leukemic blasts at undifferentiated stages and therefore maintain a larger number of LSCs in the bone marrow. 34 It has been shown that silencing HIF-1 α in Jurkat cells significantly decreased their migration and infiltration capacity.…”

Section: Discussionmentioning

confidence: 99%

Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors

et al. 2013

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Leukemia stem cells (LSCs) are considered to be the main reason for relapse and are also regarded as a major hurdle for the success of acute myeloid leukemia chemotherapy. Thus, new drugs targeting LSCs are urgently needed. Triptolide (TPL) is cytotoxic to LSCs. Low dose of TPL enhances the cytotoxicity of idarubicin (IDA) in LSCs. In this study, the ability of TPL to induce apoptosis in leukemic stem cell (LSC)-like cells derived from acute myeloid leukemia cell line KG1a was investigated. LSC-like cells sorted from KG1a were subjected to cell cycle analysis and different treatments, and then followed by in vitro methyl thiazole tetrazolium bromide cytotoxicity assay. The effects of different drug combinations on cell viability, intracellular reactive-oxygen species (ROS) activity, colony-forming ability and apoptotic status were also examined. Combination index-isobologram analysis indicates a synergistic effect between TPL and IDA, which inhibits the colony-forming ability of LSC-like cells and induces their apoptosis. We further investigated the expression of Nrf2, HIF-1α and their downstream target genes. LSC-like cells treated with both TPL and IDA have increased levels of ROS, decreased expression of Nrf2 and HIF-1α pathways. Our findings indicate that the synergistic cytotoxicity of TPL and IDA in LSCs-like cells may attribute to both induction of ROS and inhibition of the Nrf2 and HIF-1α pathways.

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“…One significant hurdle for the use of these compounds, however, is the lack of specificity of these compounds for specific blockade of HIF (such as digoxin, acriflavine, and 17-AAG) identified to date [124–126]. Despite these caveats, therapies designed to interfere with HIF signaling in tumors are already in clinical trials in humans to assess antitumor efficacy [127]. …”

Section: Therapeutic Potential Of the Hypoxic Pathwaymentioning

confidence: 99%

Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function

et al. 2012

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Oxygen is a molecule that is central to cellular respiration and viability, yet there are multiple physiologic and pathological contexts in which cells experience conditions of insufficient oxygen availability, a state known as hypoxia. Given the metabolic challenges of a low oxygen environment, hypoxia elicits a range of adaptive responses at the cellular, tissue, and systemic level to promote continued survival and function. Within this context, T lymphocytes are a highly migratory cell type of the adaptive immune system that frequently encounters a wide range of oxygen tensions in both health and disease. It is now clear that oxygen availability regulates T cell differentiation and function, a response orchestrated in large part by the hypoxia-inducible factor transcription factors. Here, we discuss the physiologic scope of hypoxia and hypoxic signaling, the contribution of these pathways in regulating T cell biology, and current gaps in our understanding. Finally, we discuss how emerging therapies that modulate the hypoxic response may offer new modalities to alter T cell function and the outcome of acute and chronic pathologies.

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Targeting NF-κB and HIF-1 Pathways for the Treatment of Cancer: Part II

Cited by 29 publications

References 70 publications

On the Pro-Metastatic Stress Response to Cancer Therapies: Evidence for a Positive Co-Operation between TIMP-1, HIF-1α, and miR-210

On the Pro-Metastatic Stress Response to Cancer Therapies: Evidence for a Positive Co-Operation between TIMP-1, HIF-1α, and miR-210

Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors

Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function

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