Overexpression of beclin1 induced autophagy and apoptosis in lungs of K-rasLA1 mice

Shin, Ji Young; Hong, Sun; Kang, Bitna; Minai-Tehrani, Arash; Cho, Myung‐Haing

doi:10.1016/j.lungcan.2013.05.009

Cited by 31 publications

(22 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…studies have reported that beclin 1 is absent or expressed at very low levels in a wide variety of human tumors, and mutations in the beclin 1 gene have been detected in numerous types of cancer (2,13,(22)(23)(24)(25). A previous study demonstrated that ectopic expression of beclin 1 in MCF-7 cells activates autophagy, inhibits cellular proliferation and clonogenicity, and suppresses tumorigenesis in mouse xenograft models (26).…”

Section: Discussionmentioning

confidence: 99%

Effect of beclin 1 expression on the biological behavior and chemotherapy sensitivity of cervical cancer cells

et al. 2016

View full text Add to dashboard Cite

Abstract. The present study aimed to evaluate the effect of the expression of the autophagic gene beclin 1 on the biological behavior and chemotherapy sensitivity towards Taxol ® of cervical cancer HeLa cells. A beclin 1 expression vector was constructed and tranfected into HeLa cells. Reverse transcription-polymerase chain reaction and western blotting were used to detect the expression of beclin 1. Cell proliferation was detected based on the growth curve of the cells. The effect of beclin 1 expression on cell apoptosis was analyzed using Hoechst 33258 staining, which enabled to observe the morphology of apoptotic cells. Apoptosis-associated proteins were measured by western blot assay. The sensitivity of HeLa cells to Taxol ® was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Beclin 1 expression at the messenger RNA and protein levels was elevated following transfection of the beclin 1 expression plasmid (P<0.05). Hoechst 33258 staining revealed that the apoptosis rate of the transfected HeLa cells was significantly higher than that of normal HeLa cells. The expression of caspase-3 was increased in the transfected cells, and beclin 1 transfection increased B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax):Bcl-2 ratio, resulting in Bax activation and Bcl-2 suppression (P<0.05). Chemotherapy sensitivity analysis demonstrated that the half maximal inhibitory concentration values of Taxol ® of the transfection, non-transfection and mock-vehicle groups were 30.4, 118.0 and 125.5 µg/ml, respectively. Beclin 1 inhibited proliferation and increased apoptosis of HeLa cells, and also increased the chemosensitivity of these cells to Taxol ® . The present results confirmed that beclin 1 is a favorable prognostic biomarker for cervical cancer treatment, and may serve to identify particular patients for individual therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of beclin 1 expression on the biological behavior and chemotherapy sensitivity of cervical cancer cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Reduced expression of autophagic molecules such as Beclin1 or Bif1 in mice renders mice prone to the development of lymphoma (35). Heterozygous loss of beclin1 in human breast cancer is linked to oncogenesis, whereas overexpression of Beclin1 suppresses growth of cancer in mice (36), defining its role as a tumor suppressor. In opposition to the tumor suppressive role of autophagy, studies have also shown that the fundamental cytoprotective role of autophagy may contribute to chemotherapy resistance (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Tid1, the Mammalian Homologue of Drosophila Tumor Suppressor Tid56, Mediates Macroautophagy by Interacting with Beclin1-containing Autophagy Protein Complex

Niu

Zhang

Liu

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Furthermore, the essential autophagy component beclin-1 inhibits tumorigenesis of breast carcinoma cells, and monoallelic deletion of beclin-1 is associated with an enhanced risk of breast cancer (13-15). Increased levels of beclin-1 are associated with reduced proliferation, survival, and tumorigenesis in Ras-driven cells (16)(17)(18), suggesting that autophagy may be antitumorigenic in this context.Conversely, macroautophagy also has been reported to promote tumorigenesis of Ras-driven cancers, and inhibition of macroautophagy by either chloroquine or shRNA-mediated knockdown of ATG5 or ATG7 suppresses the proliferation of Ras-driven cancer lines in vitro and in vivo (19-21). Loss of ATG5 or ATG7 delays spontaneous tumorigenesis in genetically modified mouse models of lung and pancreatic Kirsten rat sarcoma (KRAS)-driven cancer (22-26); however, the loss of autophagy accelerated tumor onset if combined with a codeletion of p53 (25).…”

mentioning

confidence: 99%

Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy

Eng

Wang

Tkach

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

202

189

View full text Add to dashboard Cite

Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic lossof-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagyrelated 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.M acroautophagy is a catabolic pathway that shuttles cytoplasmic components via double-membrane vesicles (autophagosomes) into lysosomes for degradation and recycling. Autophagosome formation and elongation are facilitated by ubiquitin-like molecules such as MAP1LC3A/B (herein referred to as "LC3") and its homologs which are directly conjugated to phosphatidylethanolamine (PE), a reaction which requires the ubiquitin E1-like activity of autophagy-related 7 (ATG7), the E2-like activity of ATG3, and the E3-like activity of the ATG5-ATG12-ATG16L1 complex (1). Autophagy cargo receptors such as p62/ SQSTM1 bind both LC3 and ubiquitinated cargo, enabling cargo recruitment into autophagosomes and delivery to lysosomes (2, 3).Basal levels of macroautophagy control cellular homeostasis by clearing misfolded proteins or damaged organelles (4, 5). Upon starvation, macroautophagy can be induced above basal levels to supply the cell with nutrients (6, 7). This prosurvival function of macroautophagy is also used by cancer cells under conditions of metabolic stress (8). However, the role of autophagy in cancer is complex and context dependent, because the pathway has been reported to have tumor-suppressing as well as tumor-promoting properties (9-11). Liver-specific deletion of ATG7 results in increased formation of liver tumors through the activation of the Nrf2 pathway (12). Furthermore, the essential autophagy component beclin-1 inhibits tumorigenesis of breast carcinoma cells, and monoallelic deletion of beclin-1 is associated with an enhanced risk of breast cancer (13-15). I...

show abstract

Overexpression of beclin1 induced autophagy and apoptosis in lungs of K-rasLA1 mice

Cited by 31 publications

References 35 publications

Effect of beclin 1 expression on the biological behavior and chemotherapy sensitivity of cervical cancer cells

Effect of beclin 1 expression on the biological behavior and chemotherapy sensitivity of cervical cancer cells

Tid1, the Mammalian Homologue of Drosophila Tumor Suppressor Tid56, Mediates Macroautophagy by Interacting with Beclin1-containing Autophagy Protein Complex

Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy

Contact Info

Product

Resources

About