Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development

Sun, Wei‐Liang; Chen, Juan; Wang, Yanping; Zheng, Hong

doi:10.4161/auto.7.9.16521

Cited by 164 publications

(155 citation statements)

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“…The DNA synthesis inhibitor epirubicin eliminates cancer cells mainly via inducing G2/M arrest and apoptosis (39,40). The results of the present study demonstrated that, in epirubicin treated HepG2 cells, significant upregulation of the mRNA expression levels of cell cycle progression inhibitor, p21waf1/cip1, and pro-apoptosis Bax was detected (Fig.…”

Section: Discussionsupporting

confidence: 53%

Increased glyceraldehyde-3-phosphate dehydrogenase expression indicates higher survival rates in male patients with hepatitis B virus-accociated hepatocellular carcinoma and cirrhosis

Liu

Zhu

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been reported in different human malignancies. To understand its role in hepatitis B virus (HBV) infection-associated hepatocellular carcinoma (HCC), the expression of GAPDH was quantitatively measured in a cohort of 72 male HCC patients without preoperative treatment, all with evidence of chronic HBV infection. Using C-terminal banding protein 1 (CTBP1) or hypoxanthine phosphori bosyltransferase 1 (HPRT1) as reference genes, the level of GAPDH mRNA in tumor tissue was found to be significantly higher compared with that in paired non tumor tissues (P=0.0087 for CTBP1; P=0.0116 for HPRT1). Accordingly, compared with the non-tumor tissue, 37.5% (27/72) of patients' tumor tissues had a more than 2-fold increase of GAPDH expression. Furthermore, following knockdown GAPDH expression via siRNA transient transfection, HepG2 cells exhibited enhanced resistance to cytosine arabinoside (IC 50 , 308.28 µM vs. 67.68 µM in the control; P=0.01). Notably, higher GAPDH expression was significantly associated with lower liver fibrosis score (P= 0.0394) and a tendency towards higher survival rates for patients with HCC. To the best of our knowledge, the present study is the first study to report that the elevated expression levels of GAPDH in HCC tumor tissue may be relevant to an improved fibrosis score and survival probability in male patients with HBV infection; however, the underlying mechanism requires further investigation. IntroductionHepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality in males and the sixth leading cause in females worldwide (1). In addition, HCC is ranked as the second leading cause of cancer-related mortality in China (2). Over 50% of the annual HCC cases reported worldwide are diagnosed in the Chinese population (3), while hepatitis B virus (HBV) infection is responsible for 80% of all HCC causes in China (4). While a number of studies have revealed that HBV infection is the key pathogenic factor for the development of HCC, male gender and cirrhosis have also been found to be independent risk factors for the occurrence of HCC (5-7). However, few studies exist on patients presenting all these risk factors.Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was initially considered to be an essential glycolytic enzyme that is expressed in all prokaryotic and eukaryotic organisms. GADPH plays a major role in cellular metabolism, converting glyceraldehyde-3-phosphate to 1,3-diphosphoglycerate (8). In addition, studies have demonstrated that GAPDH is involved in certain important physiological functions, including the transport of transfer RNA (9), translational control (10)

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Section: Discussionsupporting

confidence: 53%

Increased glyceraldehyde-3-phosphate dehydrogenase expression indicates higher survival rates in male patients with hepatitis B virus-accociated hepatocellular carcinoma and cirrhosis

Liu

Zhu

et al. 2015

Experimental and Therapeutic Medicine

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“…Autophagy has also been implicated in the development of trastuzumab resistance in human epidermal growth factor receptor 2-positive breast cancer (30). A number of chemotherapeutic agents (anthracyclines and taxanes) are able to induce autophagy, and inhibition of autophagy increases drug toxicity via the induction of apoptosis in breast cancer cells (31,32).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

Zhu

et al. 2015

Oncology Letters

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Abstract. Heme oxygenase-1 (HMOX-1) is a microsomal enzyme that exerts anti-apoptotic and cytoprotective effects. In the present study, HMOX-1 was demonstrated to be overexpressed and able to be induced by doxorubicin in breast cancer cell lines. Knockdown of HMOX-1 using short interfering (si)RNA enhanced the cytotoxicity of doxorubicin in MDA-MB-231 and BT549 cells. Knockdown of HMOX-1 downregulated B cell lymphoma (Bcl)-2 and Bcl-extra large expression, and significantly enhanced doxorubicin-induced apoptosis in MDA-MB-231 and BT549 cells. Additionally, knockdown of HMOX-1 upregulated light chain 3B expression and markedly increased the accumulation of autophagic vacuoles in MDA-MB-231 and BT549 cells treated with doxorubicin. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy. Therefore, HMOX-1 may represent a potential therapeutic target for enhancing the cytotoxicity and efficacy of doxorubicin during the treatment of breast cancer. IntroductionBreast cancer is the most frequently diagnosed cancer amongst females and the second most common cause of cancer-related mortality among women (1). One third of novel cancer diagnoses in females are breast cancer and a total of one in eight women will be diagnosed with breast cancer, with a lifetime risk of mortality due to breast cancer of 3.4% (1). Chemotherapy is one of the major systemic therapies available for the treatment of breast cancer. A recent meta-analysis of the outcome of 100,000 patients with breast cancer, confirmed the benefit of cyclophosphamide-, methotrexate-and fluorouracil-therapies and anthracycline-based therapies with absolute reduction of mortalities of 6.2 and 6.5%, respectively, at 10 years (2). Despite progress in the improvement of chemotherapeutic strategies, the ability to treat advanced breast cancer remains poor, mainly due to the chemoresistance of cancer cells to standard chemotherapy. Numerous anti-apoptotic and cytoprotective pathways have been associated with the chemoresistance of cancer cells (3,4).Heme oxygenase (HMOX) is a microsomal enzyme, which catalyzes the initial, rate-limiting step in the degradation of heme, and has a crucial role in the recycling of iron (5). The enzymatic activity of HMOX also produces CO, ferrous iron and biliverdin. Thus, HMOX is able to reduce oxidative stress, attenuate inflammatory responses and lower the rate of apoptosis (6). HMOX-1, an isoform of HMOX, may be induced in response to cellular stress and diverse oxidative stimuli (7). HMOX-1 is frequently overexpressed in a range of cancers, including hepatoma, prostate cancer, melanoma and brain tumors (8-11). HMOX-1 promotes proliferation in human melanoma and pancreatic cancer cell lines (10,12). As HMOX-1 is a potent inducer of vascular endothelial growth factor (VEGF), a crucial factor involved in tumor angiogenesis, it has also been recognized to stimulate angiogenesis and thus support tumor progression (13). Additionally, overexpression of...

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“…Autophagy is a highly conserved cellular degradation process that eliminates aggregated or unfolded/misfolded proteins and damaged organelles in response to stress or nutrient deprivation (17)(18)(19). It was shown that autophagy provided protection for breast cancer cells against epirubicin, an anthracycline drug used for chemotherapy, and inhibition of autophagy resensitized the MCF-7 cells to epirubicin (20). Moreover, accumulative studies imply that the UPR may involve the induction of autophagy under cellular stress (21)(22)(23)(24).…”

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confidence: 99%

Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy

Chang

Wang

2016

Journal of Biological Chemistry

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Chemoresistance is a major barrier to effective chemotherapy of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Recently, autophagy, a highly conservative intracellular recycling system, has shown to be associated with chemoresistance in cancer cells. However, little is known about how autophagy plays a role in the development of chemoresistance in HNSCC and how autophagy is initiated when HNSCC cells undergo cytotoxic stress. Here, we report that autophagy was activated when HNSCC cells are treated with the proteasome inhibitor bortezomib, proposed as an alternative chemotherapeutic agent for both primary and cisplatin-resistant HNSCC cells. Ablation of histone deacetylase 6 (HDAC6) expression and its activity in HNSCC cells significantly inhibited autophagy induction by altering the phosphorylation status of mammalian target of rapamycin and enhanced the bortezomib cytotoxicity. Similarly, a combination regimen of bortezomib and the histone deacetylase inhibitor trichostatin A abolished HDAC6 activity and decreased autophagy induction while significantly enhancing bortezomib-induced apoptosis in HNSCC cells. These data uncover a novel molecular mechanism indicating that HDAC6 may serve as a critical causal link between autophagy, apoptosis, and the cell survival response in HNSCC. A combination regimen resulting in regression of autophagy improves chemotherapeutic efficacy, thereby providing a new strategy to overcome chemoresistance and to improve the treatment and survival of HNSCC patients.

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Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development

Abstract: (2011) Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development,

Cited by 164 publications

References 38 publications

Increased glyceraldehyde-3-phosphate dehydrogenase expression indicates higher survival rates in male patients with hepatitis B virus-accociated hepatocellular carcinoma and cirrhosis

Increased glyceraldehyde-3-phosphate dehydrogenase expression indicates higher survival rates in male patients with hepatitis B virus-accociated hepatocellular carcinoma and cirrhosis

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy

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