Activated α2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses

Misra, U. K.; Pizzo, Salvatore V.

doi:10.1074/jbc.m114.617837

Cited by 27 publications

(15 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cell surface GRP78 has been implicated in the progression of many human cancers including melanoma, breast, prostate cancer and hepatocellular carcinoma [ 9 ]. Lots of data have linked cell surface GRP78 to pro-proliferative and anti-apoptotic signaling pathway [ 33 ]. However, the role of cell surface GRP78 in tumor invasion and metastasis remains poor documented.…”

Section: Discussionmentioning

confidence: 99%

The role of c-Src in the invasion and metastasis of hepatocellular carcinoma cells induced by association of cell surface GRP78 with activated α2M

Zhao

Wang

et al. 2015

BMC Cancer

View full text Add to dashboard Cite

BackgroundEmerging data have suggested that cell surface GRP78 is a multifunctional receptor and has been linked to proliferative and antiapoptotic signaling cascades. Activated α2−macroglobin (α2M*) is a natural circulating ligand of cell surface GRP78. Association of cell surface GRP78 with α2M* is involved in the regulation of cell proliferation, survival and apoptosis in human cancers.MethodsThe invasion and metastasis of HCC cells were examined using transwell and wound healing assay; Cell surface expression of GRP78 was detected by in cell western assay. Translocation of GRP78 from cytosol to cell surface was observed by transfection of GRP78-EGFP plus TRIRC-WGA staining. The levels of Src, phosphor-Src, FAK, phospho-FAK, EGFR, phospho-EGFR, phospho-Cortactin, phospho-Paxillin were determined by western blot. Cell surface expression of GRP78 in HCC tissue samples was observed by immunofluorescence. The distribution of Paxillin and Cortactin in HCC cells was also observed by immunofluorescence. The interaction between GRP78 and Src were detected by far-western blot, co-immunoprecipitation and GST pulldown. GRP78 mRNA was detected by RT-PCR.ResultsIn the current study, we showed that association of cell surface GRP78 with α2M* stimulated the invasion and metastasis of HCC. Cell surface GRP78 could interact directly with c-Src, promoted the phosphorylation of c-Src at Y416. Inhibition of the tyrosine kinase activity of c-Src with PP2 reverted the stimulatory effect caused by association of cell surface GRP78 with α2M*. Moreover, association of cell surface GRP78 with α2M* facilitates the interaction between EGFR and c-Src and consequently phosphorylated EGFR at Y1101 and Y845, promoting the invasion and metastasis of HCCs. However, inhibition of the tyrosine kinase of c-Src do not affect the interaction between EGFR and Src.Conclusionc-Src plays a critical role in the invasion and metastasis of HCC induced by association of cell surface GRP78 with α2M*. Cell surface GRP78 directly binds and phosphorylates c-Src. As a consequence, c-Src phosphorylated EGFR, promoting the invasion and metastasis of HCCs.

show abstract

Section: Discussionmentioning

confidence: 99%

The role of c-Src in the invasion and metastasis of hepatocellular carcinoma cells induced by association of cell surface GRP78 with activated α2M

Zhao

Wang

et al. 2015

BMC Cancer

View full text Add to dashboard Cite

show abstract

“…Consequently, the anticancer potential of fatostatin has been investigated. In prostate cancer cell lines, fatostatin inhibits cell proliferation and insulin-stimulated protein and DNA synthesis (18,40,41). These effects have been attributed to fatostatin inhibition of SCAP-and SREBP-dependent transcription.…”

Section: Downloaded Frommentioning

confidence: 99%

Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner

Shao

Machamer

Espenshade

2016

Journal of Lipid Research

View full text Add to dashboard Cite

“…Importantly, targeting CS-GRP78 by C38 or other specific monoclonal antibodies inhibits tumor growth in murine xenograft models of various tumors [ 28 , 31 , 35 ]. In addition, recently we reported that the α 2 M * /CS-GRP78 axis regulates metabolic alterations to enhance aerobic glycolysis and induce fatty acid synthesis in prostate cancer cells [ 36 ]. However, it is not known whether the α 2 M * /CS-GRP78 axis contributes to histone acetylation by regulating metabolic reprogramming.…”

Section: Introductionmentioning

confidence: 99%

Cell surface GRP78 promotes tumor cell histone acetylation through metabolic reprogramming: a mechanism which modulates the Warburg effect

Gopal

Pizzo

2017

Oncotarget

View full text Add to dashboard Cite

Acetyl coenzyme A (acetyl-CoA) is essential for histone acetylation, to promote cell proliferation by regulating gene expression. However, the underlying mechanism(s) governing acetylation remains poorly understood. Activated α2-Macroglobulin (α2M*) signals through tumor Cell Surface GRP78 (CS-GRP78) to regulate tumor cell proliferation through multiple signaling pathway. Here, we demonstrate that the α2M*/CS-GRP78 axis regulates acetyl-CoA synthesis and thus functions as an epigenetic modulator by enhancing histone acetylation in cancer cells. α2M*/CS-GRP78 signaling induces and activates glucose-dependent ATP-citrate lyase (ACLY) and promotes acetate-dependent Acetyl-CoA Synthetase (ACSS1) expression by regulating AKT pathways to acetylate histones and other proteins. Further, we show that acetate itself regulates ACLY and ACSS1 expression through a feedback loop in an AKT-dependent manner. These studies demonstrate that α2M*/CS-GRP78 signaling is a central mechanism for integrating glucose and acetate-dependent signaling to induce histone acetylation. More importantly, targeting the α2M*/CS-GRP78 axis with C38 Monoclonal antibody (Mab) abrogates acetate-induced acetylation of histones and proteins essential for proliferation and survival under hypoxic stress. Furthermore, C38 Mab significantly reduced glucose uptake and lactate consumption which definitively suggests the role of aerobic glycolysis. Collectively, besides its ability to induce fatty acid synthesis, our study reveals a new mechanism of epigenetic regulation by the α2M*/CS-GRP78 axis to increase histone acetylation and promote cell survival under unfavorable condition. Therefore CS-GRP78 might be effectively employed to target the metabolic vulnerability of a wide spectrum of tumors and C38 Mab represents such a potential therapeutic agent.

show abstract

Activated α2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses

Cited by 27 publications

References 90 publications

The role of c-Src in the invasion and metastasis of hepatocellular carcinoma cells induced by association of cell surface GRP78 with activated α2M

The role of c-Src in the invasion and metastasis of hepatocellular carcinoma cells induced by association of cell surface GRP78 with activated α2M

Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner

Cell surface GRP78 promotes tumor cell histone acetylation through metabolic reprogramming: a mechanism which modulates the Warburg effect

Contact Info

Product

Resources

About