Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy

Qiu, Yu; Peng, Li; Ji, Chunyan

doi:10.3390/ijms161025536

Cited by 42 publications

(33 citation statements)

References 90 publications

(111 reference statements)

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“…Our results demonstrated that there is no significant difference in autophagy induction in neoplastic tissue when compared to normal testicular tissue. Contrary to these findings, apoptotic activity is significantly increased in testicular tumor, but not in normal testicular tissue, as proliferative tumor tissue of a certain size usually becomes hypoxic, eventually necrotic and thus enhanced apoptosis can be detected particularly at the margins of hypoxic or necrotic tumor areas (31,32). Up to now the loco-regional expression patterns of autophagy in TGCTs have not been a subject of research.…”

Section: Discussionmentioning

confidence: 86%

“…Autophagy induction in cancer cells may occur due to hypoxia (13,32), and it has been previously demonstrated that expression of hypoxiainducible factor 1α (HIF-1α) downstream targets is associated with a higher histologic grade in fibroepithelial tumors of the breast (33). In this scenario autophagy provides the nutrients needed for cancer survival and stabilization of HIF-1α allows for instance that higher grade phyllode tumors adapt to hypoxia (30).…”

Section: Discussionmentioning

confidence: 99%

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Autophagy-associated proteins BAG3 and p62 in testicular cancer

et al. 2015

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Abstract. Testicular germ cell tumors (TGCT) represent the most common malignant tumor group in the age group of 20 to 40-years old men. The potentially curable effect of cytotoxic therapy in TGCT is mediated mainly by the induction of apoptosis. Autophagy has been discussed as an alternative mechanism of cell death but also of treatment resistance in various types of tumors. However, in TGCT the expression and role of core autophagy-associated factors is hitherto unknown. We designed the study in order to evaluate the potential role of autophagy-associated factors in the development and progression of testicular cancers. Eighty-four patients were assessed for autophagy (BAG3, p62) and apoptosis (cleaved caspase 3) markers using immunohistochemistry (IHC) on tissue microarrays. In addition, western blot analyses of frozen tissue of seminoma and non-seminoma were performed. Our findings show that BAG3 was significantly upregulated in seminoma as compared to non-seminoma but not to normal testicular tissue. No significant difference of p62 expression was detected between neoplastic and normal tissue or between seminoma and non-seminoma. BAG3 and p62 showed distinct loco-regional expression patterns in normal and neoplastic human testicular tissues. In contrast to the autophagic markers, apoptosis rate was significantly higher in testicular tumors as compared to normal testicular tissue, but not between different TGCT subtypes. The present study, for the first time, examined the expression of central autophagy proteins BAG3 and p62 in testicular cancer. Our findings imply that in general apoptosis but not autophagy induction differs between normal and neoplastic testis tissue. IntroductionThe effect of cytotoxic treatment in testicular tumors is mainly moderated by the induction of apoptosis (1). Due to the rapid response after exposure to chemotherapeutic agents an intact and effective apoptotic pathway in most testicular cancers is assumed (2). Nevertheless, various patients show complex clinical courses, including tumors with chemoresistence and thus lower apoptosis rates (3). Recent studies have shown that the elimination of cells may be also conducted using the alternative cell death pathway ʻautophagyʼ (4,5).Autophagy is an evolutionarily conserved, pervasive and multi-step ʻself-eatingʼ process, by which cytosolic material is sequestered in a double-lipid membrane, delivered to the lysosome for degradation and digested to provide energy and to build the foundation for cell-survival (6). While autophagy has for long been considered to be a bulk degradation process, recent discoveries show that it rather displays a sophisticated portfolio of selectivity provided by different molecular strategies such as the detection of several autophagy receptor proteins, including pacemaker molecules such as p62 (SQSTM1) and BCL2-associated athanogene 3 (BAG3) (7-9). To the best of our knowledge, no study has been published to date that examined the expression of the cohesive autophagy proteins BAG3 and p62 in testicular can...

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Autophagy-associated proteins BAG3 and p62 in testicular cancer

et al. 2015

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“…HIF-1 controls the expression of several downstream genes, which affect energy metabolism, glycolysis, angiogenesis, DNA repair, and the cell cycle progression. These genes not only control tumor proliferation and metastasis, but also promote chemotherapy resistance (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

et al. 2018

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Overcoming the chemoresistance of bladder cancer is a pivotal obstacle in clinical treatments. Hypoxia widely exists in solid tumors and has been demonstrated to contribute to chemoresistance through hypoxia-inducible factor 1α (HIF‑1α)-mediated autophagy in several types of cancer. However, it is unclear whether HIF‑1α-mediated autophagy and chemoresistance occur in bladder cancer. The present study demonstrated that HIF‑1α was overexpressed in 20 bladder cancer tissues compared with matched paracarcinoma tissues. Gemcitabine-induced apoptosis during hypoxia was significantly reduced compared with that observed under normoxic conditions. In addition, hypoxia activated autophagy and enhanced gemcitabine-induced autophagy. Combined treatment using gemcitabine and an autophagy inhibitor (3-methyladenine) under hypoxia significantly increased gemcitabine cytotoxicity. Furthermore, it was demonstrated that hypoxia-activated autophagy depended on the HIF‑1α/BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)/Beclin1 signaling pathway. Suppressing HIF‑1α inhibited autophagy, BNIP3 and Beclin1, as well as enhanced gemcitabine-induced apoptosis in bladder cancer cells under hypoxic conditions. Consequently, the results of the present study demonstrated that hypoxia-induced cytoprotective autophagy counteracted gemcitabine-induced apoptosis through increasing HIF‑1α expression. Therefore, targeting HIF‑1α-associated pathways or autophagy in bladder cancer may be a successful strategy to enhance the sensitivity of bladder cancer chemotherapy.

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“…The phosphoinositide 3-kinases (PI3K)/Akt (also known as PKB) signaling pathway is considered to be involved in the regulation of cellular activation and apoptosis (11). Investigations have indicated that the PI3K/Akt signaling pathway can elevate cellular viability by limiting the apoptotic events induced by noxious stimuli (12).…”

Section: Introductionmentioning

confidence: 99%

Schisandrin B protects against myocardial ischemia/reperfusion injury via the PI3K/Akt pathway in rats

et al. 2017

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The natural medicinal monomer, schisandrin B (Sch B), has been shown to exert cardioprotective effects; however, the underlying mechanisms of these effects remain to be fully elucidated. Therefore, the aim of the present study was to investigate whether Sch B attenuated myocardial ischemia/reperfusion (I/R) injury via the phosphoinositide 3‑kinases (PI3K)/Akt signaling pathway. To confirm this, I/R models were established in rats by ligation of the left anterior descending coronary artery. A group of animals were administered with Sch B (60 mg/kg, lavage) and/or the PI3K inhibitor, LY294002 (0.3 mg/kg, intraperitoneal). Myocardial infarct size, myocardial infarct serum markers, myocardial apoptotic index and the expression of Akt were measured in each group. The results demonstrated that the administration of Sch B reduced the size of the myocardial infarct, and this effect was eliminated following LY294002 treatment. In addition, the administration of Sch B decreased the apoptotic index and the serum markers of myocardial infarction. Sch B administration also increased the expression of phosphorylated Akt, and Sch B treatment decreased the B‑cell lymphoma 2 (Bcl‑2)‑like protein 4/Bcl‑2 ratio and the expression of cleaved caspase‑3. Therefore, Sch B may protect myocardial tissue from I/R injury via the PI3K/Akt signaling pathway in rats.

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Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy

Cited by 42 publications

References 90 publications

Autophagy-associated proteins BAG3 and p62 in testicular cancer

Autophagy-associated proteins BAG3 and p62 in testicular cancer

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

Schisandrin B protects against myocardial ischemia/reperfusion injury via the PI3K/Akt pathway in rats

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