Endostar down-regulates HIF-1 and VEGF expression and enhances the radioresponse to human lung adenocarcinoma cancer cells

Zhang, Ling; Ge, Wei; Hu, Ke; Zhang, Yanyan; Li, Changhu; Xu, Ximing; He, Du; Zhao, Zhenyu; Zhang, J. Z.; Jie, Fangfang; Chen, Yu; Yang, Zheng

doi:10.1007/s11033-011-0713-6

Cited by 38 publications

(34 citation statements)

References 25 publications

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“…Keywords: hypoxia; hypoxia-inducible factors; tumorigenesis; E3 ligase; linear ubiquitin chain assembly complex Rapidly proliferating cancers, including lung adenocarcinoma and glioblastoma multiforme (GBM), must adapt to tissue hypoxia, which develops in the central regions of tumors (1)(2)(3). This is largely accomplished by a program activated in response to the stabilization of hypoxiainducible factors (HIFs), which act as transcription factors to induce metabolic changes and preserve cellular energy homeostasis (4)(5)(6).…”

Section: Measurements and Main Resultsmentioning

confidence: 99%

“…This is largely accomplished by a program activated in response to the stabilization of hypoxiainducible factors (HIFs), which act as transcription factors to induce metabolic changes and preserve cellular energy homeostasis (4)(5)(6). The importance of HIFs in tumorigenesis is experimentally well established and therapies directed at some HIF target genes are being clinically evaluated (3,7,8).…”

Section: Measurements and Main Resultsmentioning

confidence: 99%

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HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

Queisser

Dada

Deiss-Yehiely

et al. 2014

Am J Respir Crit Care Med

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Rationale: Protein kinase C zeta (PKCz) has been reported to act as a tumor suppressor. Deletion of PKCz in experimental cancer models has been shown to increase tumor growth. However, the mechanisms of PKCz down-regulation in cancerous cells have not been previously described.Objectives: To determine the molecular mechanisms that lead to decreased PKCz expression and thus increased survival in cancer cells and tumor growth.Methods: The levels of expression of heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), HOIL-1-interacting protein (HOIP), Shank-associated RH domain-interacting protein (SHARPIN), and PKCz were analyzed by Western blot and/or quantitative real-time polymerase chain reaction in different cell lines. Coimmunoprecipitation experiments were used to demonstrate the interaction between HOIL-1L and PKCz. Ubiquitination was measured in an in vitro ubiquitination assay and by Western blot with specific antibodies. The role of hypoxia-inducible factor (HIF) was determined by gain/loss-of-function experiments. The effect of HOIL-1L expression on cell death was investigated using RNA interference approaches in vitro and on tumor growth in mice models. Increased HOIL-1L and decreased PKCz expression was assessed in lung adenocarcinoma and glioblastoma multiforme and documented in several other cancer types by oncogenomic analysis. Measurements and Main Results:Hypoxia is a hallmark of rapidly growing solid tumors. We found that during hypoxia, PKCz is ubiquitinated and degraded via the ubiquitin ligase HOIL-1L, a component of the linear ubiquitin chain assembly complex (LUBAC). In vitro ubiquitination assays indicate that HOIL-1L ubiquitinates PKCz at Lys-48, targeting it for proteasomal degradation. In a xenograft tumor model and lung cancer model, we found that silencing of HOIL-1L increased the abundance of PKCz and decreased the size of tumors, suggesting that lower levels of HOIL-1L promote survival. Indeed, mRNA transcript levels of HOIL-1L were elevated in tumor of patients with lung adenocarcinoma, and in a lung adenocarcinoma tissue microarray the levels of HOIL-1L were associated with high-grade tumors. Moreover, we found that HOIL-1L expression was regulated by HIFs. Interestingly, the actions of HOIL-1L were independent of LUBAC.Conclusions: These data provide first evidence of a mechanism of cancer cell adaptation to hypoxia where HIFs regulate HOIL-1L, which targets PKCz for degradation to promote tumor survival. We provided a proof of concept that silencing of HOIL-1L impairs lung tumor growth and that HOIL-1L expression predicts survival rate in cancer patients suggesting that HOIL-1L is an attractive target for cancer therapy.

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Section: Measurements and Main Resultsmentioning

confidence: 99%

Section: Measurements and Main Resultsmentioning

confidence: 99%

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

Queisser

Dada

Deiss-Yehiely

et al. 2014

Am J Respir Crit Care Med

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“…For example, HIF-1α inhibits apoptosis and promotes the proliferation of lung cancer cells (Volm and Koomagi, 2000;Fan et al, 2002), regulates the tolerance to palladium drugs (Song et al, 2006), promotes angiogenesis in lung cancer (Jackson et al, 2010), promotes the proliferation of cancer cells (Wang et al, 2013), and promotes the migration of lung cancer cells (Li et al, 2009b). HIF-1α expression is significantly upregulated after surgery or radiotherapy (Zhang et al, 2009); therefore, HIF-1α may serve as a biomarker to evaluate prognosis (Luan et al, 2013;Wang et al, 2014b), or serve as a target for treatment (Jacoby et al, 2010;Zhang et al, 2012). However, the role of HIF-2α in lung cancer has rarely been reported on.…”

Section: Introductionmentioning

confidence: 99%

High expression of HIF-2α and its anti-radiotherapy effect in lung cancer stem cells

Sun¹,

He²,

Yi³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Hypoxia-inducible factor-2 alpha (HIF-2α) has been shown to regulate cell stemness, although the expression and effects of HIF-2α in lung cancer stem cells remained unclear. This study investigated HIF-2α expression in lung cancer stem cells, as well as the relationship between HIF-2α expression and radioresistance in lung cancer cells. Stem-like cells (CD133 + ) in the non-small-cell lung cancer cell line A549 were enriched by serum-free culture conditions, and CD133 + cells were sorted via fluorescence-activated cell sorting. A549 cells were treated with middle-infrared radiation, and the level of HIF-2α expression was determined by a quantitative polymerase chain reaction assay and western blot analysis. The level of HIF-2α expression in tissue sections from 50 cases of clinically confirmed non-small-cell lung cancer was determined via immunohistochemical analysis, and its correlation with prognosis after radiotherapy was analyzed. HIF-2α levels in CD133 + cells were significantly higher than those in CD133 -cells (P = 0.032). However, after radiation treatment, these levels were significantly upregulated in both CD133+ and CD133 -cells (P = 0.031 and P = 0.023, respectively). After irradiation, the proportions of apoptotic, dead, and autophagic CD133 + A549 cells were 18111 HIF-2α and radioresistance in lung cancer stem cells ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 18110-18120 (2015) considerably lower than those of CD133 -A549 cells (P < 0.05). Furthermore, the recovery of carcinoembryonic antigen to pre-radiation levels was more rapid in lung cancer patients with high levels of HIF-2α expression, and these patients had shorter survival times (P = 0.018). HIF-2α is highly expressed in lung cancer stem cells, which may lead to radioresistance. In conclusion, HIF-2α is a potential prognostic marker for lung cancer.

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“…A previous study of our group revealed that Endostar is involved in the radiosensitivity of lung cancer by inhibiting the expression of hypoxia-inducible factor 1α (HIF-1α) (13,14). In cancer cells, HIF-1α induces the expression and enhances the activity of several glycolytic proteins that differ from those detected in nonmalignant cells, including transporters (glucose transporters 1 and 3) and enzymes (hexokinase I and II, and phosphofructokinase-L) (15 anhydrase IX (CA IX) contributes to the acidification of the tumor environment by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons with its extracellularly situated active site.…”

Section: Introductionmentioning

confidence: 99%

Endostar enhances the antitumor effects of radiation by affecting energy metabolism and alleviating the tumor microenvironment in a Lewis lung carcinoma mouse model

Yang

et al. 2015

Oncology Letters

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Abstract. Lung cancer is a leading cause of morbidity and mortality. Previous studies have identified that an improvement in treatment efficacy was achieved using Endostar; however, the role of Endostar in lung cancer remains poorly understood. The present study investigated whether the enhanced antitumor effects of Endostar in combination with radiation involved changes in the metabolism and microenvironment in non-small cell lung cancer. A Lewis lung carcinoma mouse model was used, including the control, Endostar (ES), radiotherapy (RT) and Endostar plus radiotherapy (ES + RT) groups. The tumor inhibition rates and growth were described based on changes in tumor volume. In addition, ultraviolet enzymatic analysis was performed to determine the lactate level and reverse transcription-polymerase chain reaction was used to measure the mRNA expression of lactate dehydrogenase (LDH). A Meph-3 pH meter was used to detect the ranges of tumor interstitial tissue pH, and immunohistochemical analysis was adopted to examine hypoxia within the tumor microenvironment. The tumor inhibition rate of the ES + RT group was significantly higher compared with the other three groups (P<0.05). Following treatment, the lactate levels decreased in all three treatment groups compared with the control, particularly in the ES + RT group (P<0.05). Reduced LDH expression and hypoxic fraction in the tumor microenvironment were also observed in the ES + RT group (P<0.05). Furthermore, changes from acidic to alkaline pH in the tumor microenvironment were detected in the ES + RT group. The present study suggested that Endostar is involved in the regulation of metabolism and tumor microenvironment hypoxia, which may be responsible for the enhanced antitumor effect of Endostar in combination with radiotherapy.

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Endostar down-regulates HIF-1 and VEGF expression and enhances the radioresponse to human lung adenocarcinoma cancer cells

Cited by 38 publications

References 25 publications

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

High expression of HIF-2α and its anti-radiotherapy effect in lung cancer stem cells

Endostar enhances the antitumor effects of radiation by affecting energy metabolism and alleviating the tumor microenvironment in a Lewis lung carcinoma mouse model

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