Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor

Wu, Mei‐Yi; Fu, Junjiang; Xu, Jianming; O’Malley, Bert W.; Wu, Ray-Chang

doi:10.1038/cr.2012.44

Cited by 45 publications

(48 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results revealed that MIF siRNA significantly suppressed tumor growth in nude mice. Consistent with our finding, a recent report showed that MIF knockdown inhibited the tumorigenicity of breast cancer cells in a tumor xenograft mouse model [35]. …”

Section: Discussionsupporting

confidence: 93%

Small interfering RNA (siRNA)-mediated knockdown of macrophage migration inhibitory factor (MIF) suppressed cyclin D1 expression and hepatocellular carcinoma cell proliferation

et al. 2014

View full text Add to dashboard Cite

Macrophage migration inhibitory factor (MIF), a proinflammatory and immunoregulatory chemokine, plays important roles in cancer-related biological processes. However, few studies have focused on the clinical relevance of MIF and cyclin D1 expression in hepatocellular carcinoma cells (HCCs). In this study, MIF and cyclin D1 expression levels in HCC tissues and cell lines were significantly upregulated compared with adjacent normal tissues or a normal liver cell line. In HCC specimens, MIF expression positively correlated with cyclin D1 expression. Additionally, MIF and cyclin D1 expression positively correlated with tumor size. MIF knockdown inhibited the proliferation of PLC and HepG2 cells and promoted apoptosis. However, small interfering RNA (siRNA) against MIF did not influence the cell cycle in these cells. In an in vivo xenograft model, MIF knockdown reduced the tumor growth rate. The expression levels of Bcl-2, p-caspase-3, BIM and Bax were upregulated, while the expression levels of cyclin D1, p-Akt and p-ERK were downregulated in MIF-knockdown cells. These findings indicate that MIF siRNA reduces proliferation and increases apoptosis in HCC cells. MIF knockdown inhibits the expression of growth-related proteins and induces the expression of apoptosis-related proteins, supporting a role for MIF as a novel therapeutic target for HCC.

show abstract

Section: Discussionsupporting

confidence: 93%

Small interfering RNA (siRNA)-mediated knockdown of macrophage migration inhibitory factor (MIF) suppressed cyclin D1 expression and hepatocellular carcinoma cell proliferation

et al. 2014

View full text Add to dashboard Cite

show abstract

“…MIF has been shown to induce autophagy in cardiomyocytes, 21,22 endothelial cells 23 and a human hepatoma cell line, 24 while other work has suggested an inhibitory role for MIF on autophagy in cardiomyocytes and breast cancer cell lines. [25][26][27] Intriguingly, one study demonstrated that amino acid starvation, which induces autophagy, also induces MIF secretion, 24 but the effect of autophagy on the release of MIF remains poorly understood. However, as MIF is constitutively expressed in cells, autophagy might be a key regulator of its turnover and secretion.…”

Section: Introductionmentioning

confidence: 99%

Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages

et al. 2016

View full text Add to dashboard Cite

MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]) is a pro-inflammatory cytokine expressed in multiple cells types, including macrophages. MIF plays a pathogenic role in a number of inflammatory diseases and has been linked to tumor progression in some cancers. Previous work has demonstrated that loss of autophagy in macrophages enhances secretion of IL1 family cytokines. Here, we demonstrate that loss of autophagy, by pharmacological inhibition or siRNA silencing of Atg5, enhances MIF secretion by monocytes and macrophages. We further demonstrate that this is dependent on mitochondrial reactive oxygen species (ROS). Induction of autophagy with MTOR inhibitors had no effect on MIF secretion, but amino acid starvation increased secretion. This was unaffected by Atg5 siRNA but was again dependent on mitochondrial ROS. Our data demonstrate that autophagic regulation of mitochondrial ROS plays a pivotal role in the regulation of inflammatory cytokine secretion in macrophages, with potential implications for the pathogenesis of inflammatory diseases and cancers.

show abstract

“…Furthermore, downstream targets that are regulated at the post-transcriptional level cannot be identified from the microarray studies. In the present study, we employ a ''rescue strategy'' to identify genes downstream from SRC-3 that specifically functioned in cell resistance to cytotoxic stress using a lentiviral cDNA library screening approach (Wu et al 2012). Overexpression of the candidate gene by lentivirus is able to rescue the consequences of SRC-3 depletion on cell sensitivity to the induced stress.…”

mentioning

confidence: 99%

SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization

Xia

et al. 2013

Genes Dev.

Self Cite

View full text Add to dashboard Cite

Steroid receptor coactivator 3 (SRC-3) is an oncogenic nuclear receptor coactivator that plays a significant role in drug resistance. Using a lentiviral cDNA library rescue screening approach, we identified a SRC-3 downstream gene-TRAF4 (tumor necrosis factor [TNF] receptor associated-factor 4)-that functions in cell resistance to cytotoxic stress. TRAF4 expression is positively correlated with SRC-3 expression in human breast cancers. Similar to that observed for SRC-3 overexpression, breast cancer cells overexpressing TRAF4 are more resistant to stress-induced death. Here, we further dissected the underlying molecular mechanism for SRC-3 and TRAF4-mediated resistance to cytotoxic agents. We observed that SRC-3 expression is inversely correlated with the expression of p53-regulated proapoptotic genes in breast cancers and further found that SRC-3 and TRAF4 overexpression diminished cytotoxic stress-induced up-regulation of the tumor suppressor p53 protein.To determine the mechanism, we showed that the TRAF domain of TRAF4 bound to the N-terminal TRAF-like region of the deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease; also named USP7) and blocked the access of p53 to the same region of HAUSP. This TRAF4-mediated inhibition of HAUSP then led to the loss of p53 deubiquitination and its stabilization in response to cellular stress. Consistent with this cellular function, we also found that TRAF4 overexpression in breast cancer patients was associated significantly with poor prognosis. Because of SRC-3's ability to abrogate p53 function, our results suggest that SRC-3 overexpression may be especially important in tumors in which p53 is not mutated.

show abstract

Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor

Cited by 45 publications

References 70 publications

Small interfering RNA (siRNA)-mediated knockdown of macrophage migration inhibitory factor (MIF) suppressed cyclin D1 expression and hepatocellular carcinoma cell proliferation

Small interfering RNA (siRNA)-mediated knockdown of macrophage migration inhibitory factor (MIF) suppressed cyclin D1 expression and hepatocellular carcinoma cell proliferation

Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages

SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization

Contact Info

Product

Resources

About