Interaction between hypoxia, AKT and HIF-1 signaling in HNSCC and NSCLC: implications for future treatment strategies

Stegeman, Hanneke; Span, Paul N.; Peeters, Wenny J.M.; Verheijen, Marieke M; Grénman, Reidar; Meijer, T.; Kaanders, Johannes H.A.M.; Bussink, Johan

doi:10.4155/fso.15.84

Cited by 27 publications

(28 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been shown in serval studies that major signaling pathways including ERK and AKT pathways adjust HIF-1α [30]. These pathways have been verified to dramatically function in the molecular signaling network adjusting growth, differentiation, proliferation as well as survival in multiple cell types [31][32][33]. In our study, gain-and loss-of-function experiments of H19 were carried out to measure AXL expression in endometrial cancer cells, thus figuring out whether endometrial cancer activity is adjusted by H19 via HIF-1α/AXL signaling.…”

Section: Discussionmentioning

confidence: 97%

RETRACTED ARTICLE: Long noncoding RNA H19 regulates HIF-1α/AXL signaling through inhibiting miR-20b-5p in endometrial cancer

et al. 2019

View full text Add to dashboard Cite

In a variety of cancers, long non-coding RNAs (lncRNAs) were believed to play important roles. Nevertheless, H19's possible molecular mechanism related to miR-20b-5p has not yet been explored in endometrial cancer. Differential lncRNAs in endometrial cancer were identified based on microarray analysis (GSE23339). In this research, in the first place, H19 expression was detected to be increased but miR-20b-5p to be decreased in endometrial cancer tissues and cells. Besides, H19 expression displayed a negative relationship to miR-20b-5p expression in endometrial cancer tissues. According to gain-and loss-of-function experiments of H19, like a ceRNA, H19 elevated AXL level and HIF-1α expression so as to stimulate the migration, proliferation and EMT process of endometrial cancer. Additionally, the knockdown of H19 slowed down tumor growth, promoted apoptosis and upregulated miR-20b-5p expression but lowered the expressions of HIF-1α, PCNA and AXL in vivo. Furthermore, H19 was also verified to stimulate the activity of endometrial cancer with AXL inhibitor BGB324 in vitro and in vivo. To sum up, H19 accelerates the tumor formation of endometrial cancer through the miR-20b-5p/AXL/HIF-1α signaling pathway, thereby providing a novel target for diagnosing and treating endometrial cancer.

show abstract

Section: Discussionmentioning

confidence: 97%

RETRACTED ARTICLE: Long noncoding RNA H19 regulates HIF-1α/AXL signaling through inhibiting miR-20b-5p in endometrial cancer

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Moreover, our data also evinced that under severe levels of hypoxia, 26S proteasome turned to be a paralyzed machine in MSCs which negatively impacted their survival and proliferation by causing the accumulation of PINK1 and Parkin proteins and disturbing the mitochondrial function with the activation of apoptosis markers [47]. Several studies have reported that the survival marker P-AKT protein levels were downregulated substantially under severe levels of hypoxia, but it is maintained unaffected in moderate hypoxia [4,43,44,49]. Furthermore, it has been recently explored by one of the studies that 26S proteasome intactness is integrally pivotal in preventing the senescence of MSCs and conserving their proliferation and expansion abilities with increasing passage number [21], which goes along with our findings regarding the importance of 26S proteasome in MSCs biology and performance [24].…”

Section: Discussionsupporting

confidence: 54%

Cross talk between 26S proteasome and mitochondria in human mesenchymal stem cells’ ability to survive under hypoxia stress

et al. 2019

View full text Add to dashboard Cite

Mesenchymal stem cells (MSCs) are regarded as unique cells which play an imperative role in the field of regenerative medicine. They are characterized by the self-renewal capacity, multi-lineage differentiation abilities and immunomodulation properties which render them perfectly ideal cell type for treating a wide range of chronic diseases. Despite these enchanted features, there are many hurdles that need to be circumvented to ensure their long-term survival and viability after transplantation. Recently, hypoxia has been indicated as one of the most baffling stress conditions that can affect the survival rate of MSCs either positively or negatively depending on the level of hypoxia. MSCs can survive well under moderate hypoxia, but die shortly if they were exposed to severe hypoxia without clearly convincing explanation for this enigma. The current study reveals a novel mechanism of 26S proteasome in controlling the ability of BM-MSCs to withstand hypoxic stress by maintaining proper mitochondrial function. The results indicated that 26S proteasome remains functioning once BM-MSCs are exposed to moderate hypoxia (2.5%O 2) and preserves their survival and proliferation mediated by intact mitochondrial performance, whereas 26S proteasome becomes inactive when BM-MSCs faces severe hypoxia that lead to poor mitochondrial function and less chance to survive longer. The outcomes of this study demonstrated the importance of 26S proteasome machinery in enhancing the resistance of BM-MSCs to hypoxic stress condition which may help in better planning future studies that target this system.

show abstract

“…We then investigated the mechanism by which OGD cultured tumor cells reduced their capacity to respond to IFNy, resulting in impaired STAT1 phosphorylation. Phosphoinositide 3-kinases (PI3Ks) play pivotal roles in the regulation of cellular metabolism [33, 34] and its downstream effector AKT/PKB mediates survival of tumor cells under hypoxia [35] and protects cells from death induced by glucose deprivation [36]. This involvement of PI3K in orchestrating metabolism prompted us to examine its role in IFNγ responsiveness under OGD conditions.…”

Section: Resultsmentioning

confidence: 99%

Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling

Marijt

Sluijter

Blijleven

et al. 2019

j. immunotherapy cancer

View full text Add to dashboard Cite

Background T-cell mediated immunotherapy brought clinical success for many cancer patients. Nonetheless, downregulation of MHC class I antigen presentation, frequently occurring in solid cancers, limits the efficacy of these therapies. Unraveling the mechanisms underlying this type of immune escape is therefore of great importance. We here investigated the immunological effects of metabolic stress in cancer cells as a result of nutrient deprivation. Methods TC1 and B16F10 tumor cell lines were cultured under oxygen- and glucose-deprivation conditions that mimicked the tumor microenvironment of solid tumors. Presentation of peptide antigens by MHC class I molecules was measured by flow cytometry and via activation of tumor-specific CD8 T cell clones. The proficiency of the IFNy-STAT1 pathway was investigated by Western blots on phosphorylated proteins, transfection of constitutive active STAT1 constructs and qPCR of downstream targets. Kinase inhibitors for PI3K were used to examine its role in IFNy receptor signal transduction. Results Combination of oxygen- and glucose-deprivation resulted in decreased presentation of MHC class I antigens on cancer cells, even in the presence of the stimulatory cytokine IFNy. This unresponsiveness to IFNy was the result of failure to phosphorylate the signal transducer STAT1. Forced expression of constitutive active STAT1 fully rescued the MHC class I presentation. Furthermore, oxygen- and glucose-deprivation increased PI3K activity in tumor cells. Pharmacological inhibition of this pathway not only restored signal transduction through IFNy-STAT1 but also improved MHC class I presentation. Importantly, PI3K inhibitors also rendered tumor cells sensitive for recognition by CD8 T cells in culture conditions of metabolic stress. Conclusions These data revealed a strong impact of metabolic stress on the presentation of tumor antigens by MHC class I and suggest that this type of tumor escape takes place at hypoxic areas even during times of active T cell immunity and IFNy release. Electronic supplementary material The online version of this article (10.1186/s40425-019-0627-8) contains supplementary material, which is available to authorized users.

show abstract

Interaction between hypoxia, AKT and HIF-1 signaling in HNSCC and NSCLC: implications for future treatment strategies

Cited by 27 publications

References 29 publications

RETRACTED ARTICLE: Long noncoding RNA H19 regulates HIF-1α/AXL signaling through inhibiting miR-20b-5p in endometrial cancer

RETRACTED ARTICLE: Long noncoding RNA H19 regulates HIF-1α/AXL signaling through inhibiting miR-20b-5p in endometrial cancer

Cross talk between 26S proteasome and mitochondria in human mesenchymal stem cells’ ability to survive under hypoxia stress

Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling

Contact Info

Product

Resources

About