IBP-mediated suppression of autophagy promotes growth and metastasis of breast cancer cells via activating mTORC2/Akt/FOXO3a signaling pathway

Chen, S; Han, Qin; Wang, X; Yang, Mingzhen; Zhang, Z; Li, P; Chen, A; Hu, Chen; Li, S

doi:10.1038/cddis.2013.380

Cited by 45 publications

(41 citation statements)

References 56 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that even though doxorubicin activates mTORC1, doxorubicin-elicited inhibition of autophagy is not dependent on up-regulation of mTORC1 activity. It is also worth noting that mTORC2 is an inhibitor of autophagy (both macroautophagy 32 and chaperone-mediated autophagy 33 ). Therefore, it is likely that doxorubicin’s inhibition of autophagy in cardiomyocytes is not dependent on mTORC2 activity either.…”

Section: Resultsmentioning

confidence: 99%

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

et al. 2016

View full text Add to dashboard Cite

Background The clinical use of doxorubicin is limited by cardiotoxicity. Histopathologic changes include interstitial myocardial fibrosis and appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Methods and Results Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity due to haploinsufficiency for Beclin 1. Beclin 1+/− mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals over-expressing Beclin 1 manifested an amplified cardiotoxic response. Conclusions Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.

show abstract

Section: Resultsmentioning

confidence: 99%

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Li et al (13) revealed that IBP was highly expressed in breast cancer, but expressed at low levels in normal breast tissues, and that the ectopic expression of IBP was correlated with the malignant behavior of human breast cancer cells. Furthermore, Chen et al (32) suggested that IBP-mediated suppression of autophagy promotes the growth and metastasis of breast cancer cells by activating the mechanistic target of rapamycin kinase complex 2/protein kinase B/forkhead box O3a signaling pathway. Yang et al (33) demonstrated that IBP was a target gene of tumor protein 53 and that it suppresses cisplatin-induced apoptosis of breast cancer cells.…”

Section: Os Monthsmentioning

confidence: 99%

Overexpression and clinical significance of IBP in epithelial ovarian carcinoma

Hou

Liu

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

Abstract. Interferon regulatory factor-4 binding protein (IBP)is as a type of ρ GTPase suggested to serve an important role in tumor occurrence and development through the effects of cytoskeletal remodeling, and cell conduction mechanism. IBP is widely expressed in the immune system and expressed in several types of tumors. However, its expression and prognostic value in epithelial ovarian carcinoma (EOC) remain unclear. The present study aimed to investigate the expression of IBP in EOC, and its effect on clinicopathological variables and prognosis. A total of 107 and 30 cases of epithelial ovarian carcinoma and benign ovarian disease tissue sections, respectively, were examined using immunohistochemistry. The results indicated that the IBP expression status was negative or markedly weak in normal tissues, but highly expressed in EOC tissues. A significant association was observed between IBP overexpression and various clinicopathological factors, including advanced International Federation of Gynecology and Obstetrics stage (P<0.001), poor histologic grade (P=0.002), peritoneal carcinomatosis (P<0.001), lymph-node metastasis (P=0.023) and recurrence (P<0.001). Multivariate Cox regression analysis additionally suggested that IBP overexpression was an independent factor affecting recurrence-free survival [hazard ratio (HR)=4.099; 95% confidence interval (CI), 2.209-7.606; P<0.001) and overall survival (HR=2.317; 95% CI, 1.484-3.617; P<0.001) in patients with EOC. The results of the present study demonstrated that IBP overexpression may be associated with tumor development and progression in EOC, and therefore may serve as a novel target for treating this disease.

show abstract

“…mTORC2 was reported to regulate the actin cytoskeleton rearrangement [60]. Meanwhile, evidences certified that mTORC2 was a critical component in the regulation of cell proliferation and metastasis by the effect of autophagy [61].…”

Section: Discussionmentioning

confidence: 99%

SIRT1 promotes EMT, migration and invasion by regulating mTORC1/4E-BP1 in colorectal cancer

Peifeng

Chen

Qin

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Metastasis, rather than primary tumors, was accounted for the most cases of cancer death in colorectal cancer(CRC). The understanding of the underlying mechanism associated with tumor metastasis would improve the patient’s miserable fate. SIRT1 has been identified to play a role in tumorigenesis and progression of malignant tumors, especially in keeping the characteristics of cancer stem cells(CSCs) in CRC. This study was conducted to investigate the role of SIRT1 in the regulation of metastasis and the underlying mechanism in colorectal cancer. Methods We detected the expression of SIRT1 in 42 metastatic CRC patients. The relationship between SIRT1 and time to metastasis was also analyzed. Then the SIRT1 activity was regulated to investigate the liver metastasis in BALB/c mice. SIRT1 was knocked down to evaluate the effect on migration and invasion. Besides, exogenetic SIRT1 to assess the motile ability by wound healing assay and transwell assay. We then further explored the underlying mechanism. Results SIRT1 was overexpressed in 67% CRC metastatic patients and associated with reduced time to metastasis. High SIRT1 activity by resveratrol was companied with more liver metastasis in vivo. SIRT1 deficiency increased E-cadherin, while reduced Vimentin and Snail, attenuated migration and invasion significantly in CT26 and SW620 cells. Meanwhile, the exogenetic SIRT1 induced epithelial–mesenchymal transition (EMT) and elevated the migratory ability in SW480 cells. Further studies demonstrated that mTORC1 related genes were elevated while 4E-BP1 decayed by SIRT1 overexpression. The promotion of metastasis induced by SIRT1 overexpression could be abolished by mTOR inhibition, while the stemness of cells was not changed. Conclusions Collectively, our findings illustrated that SIRT1 was a functional regulator in the promotion of metastasis in CRC via mTORC1-4E-BP1 axis. SIRT1 was a potential independent prognostic factor of CRC metastatic patients after tumor resection, which provided a promising treatment target in CRC.

show abstract

IBP-mediated suppression of autophagy promotes growth and metastasis of breast cancer cells via activating mTORC2/Akt/FOXO3a signaling pathway

Cited by 45 publications

References 56 publications

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

Overexpression and clinical significance of IBP in epithelial ovarian carcinoma

SIRT1 promotes EMT, migration and invasion by regulating mTORC1/4E-BP1 in colorectal cancer

Contact Info

Product

Resources

About