Negative Regulation of AMP-activated Protein Kinase (AMPK) Activity by Macrophage Migration Inhibitory Factor (MIF) Family Members in Non-small Cell Lung Carcinomas

Brock, Stephanie E.; Rendon, Beatriz E.; Yaddanapudi, Kavitha; Mitchell, Robert A.

doi:10.1074/jbc.m112.378299

Cited by 39 publications

(65 citation statements)

References 46 publications

(24 reference statements)

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“…As shown in Figure 6, C and D, inhibition of MIF with ISO-1 or knockdown MIF with siRNA resulted in a pronounced reduction of phosphorylation of S6 in Pkd1 mutant renal epithelial cells, which indicated that MIF was an upstream regulator of mTOR signaling in those cells. It has been reported that mTOR activity can be inhibited by activated AMPK that accompanies metabolic stress induction by glucose restriction (23). Correspondingly, decreases in glucose uptake ( Figure 5A) and S6 phosphorylation were commensurate with increases in the phosphorylation of AMPK in Pkd1 mutant renal epithelial cells upon treatment with ISO-1 or MIF siRNA ( Figure 6, C and D).…”

Section: Mif Is a Soluble Factor Secreted By Adpkd Cells Into Adpkdcomentioning

confidence: 56%

“…Whether activation of ERK by MIF is dependent on CD74-mediated activation of SRC or other mechanisms in cystic renal epithelial cells awaits investigation. In addition, CD74 is responsible for signaling to AMPK activation by MIF (22), since silencing CD74 with siRNA had the same effects of enhanced AMPK phosphorylation as MIF silencing with siRNA in non-small cell lung carcinomas cells (23). The elevation of CD74 in Pkd1 mutant renal epithelial cells and ADPKD kidneys (Supplemental Figure 16) implies that MIF may also signal through CD74 to inhibit AMPK phosphorylation and activity in those cells.…”

Section: Discussionmentioning

confidence: 96%

“…MIF-mediated activation of ERK signaling is likely to activate the mTOR-glycolytic cascade, as has been proposed (33), which also inhibits the activation of AMPK. Inhibition of AMPK will relieve its inhibition on ERK or mTOR (23) to form double feedback loops to increase cystic epithelial cell proliferation (Figure 8). Activation of ERK signaling promotes cyst growth (35), while targeting mTOR with rapamycin or activating AMPK with metformin delays cyst growth in several different models of ADPKD (30,31).…”

Section: Methodsmentioning

confidence: 99%

“…MIF has been reported to regulate glucose uptake in non-small cell lung carcinomas (23) and to stimulate glycolysis during sepsis (40). Deprivation of glucose abrogated the higher ATP content of Pkd1 mutant mouse embryonic fibroblasts (MEFs), and glucose addition increased the intracellular ATP in these cells (33).…”

Section: Mif Is a Soluble Factor Secreted By Adpkd Cells Into Adpkdcomentioning

confidence: 99%

“…MIF regulates the cellular activities through transcriptional regulation of inflammatory gene products; modulation of cell proliferation, differentiation, cell cycle control, and metabolism; and inhibition of apoptosis (8). The proteins and pathways regulated by MIF include SRC, ERK, mTOR, AMPK, Rb, AKT, and p53, as well as TNF-α and monocyte chemotactic protein 1 (MCP-1) in different cell types (20)(21)(22)(23)(24)(25)(26)(27)(28). Notably, all the proteins and pathways listed are hyperactive in PKD (2,3,(29)(30)(31)(32)(33)(34)(35).…”

Section: Mif Expression Was Upregulated In Pkd1 Mutant Renal Epithelimentioning

confidence: 99%

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Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

et al. 2015

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Section: Mif Is a Soluble Factor Secreted By Adpkd Cells Into Adpkdcomentioning

confidence: 56%

Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Section: Mif Is a Soluble Factor Secreted By Adpkd Cells Into Adpkdcomentioning

confidence: 99%

Section: Mif Expression Was Upregulated In Pkd1 Mutant Renal Epithelimentioning

confidence: 99%

See 3 more Smart Citations

Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

et al. 2015

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D‐dopachrome tautomerase is over‐expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth

Guo

Yao

et al. 2016

Intl Journal of Cancer

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Previous studies have established the important role of MIF in the development of pancreatic ductal adenocarcinoma (PDAC) for both therapeutic and diagnostic perspectives, but little is known about the expression and function of D-dopachrome tautomerase (DDT), a functional homolog of MIF, in PDAC. In the present study, we demonstrated that DDT was over-expressed in PDAC tissues in a pattern correlated with MIF. In the pancreatic cancer cell lines, PANC-1, BXPC-3 and ASPC-1, both DDT and MIF were expressed and co-localized with each other in the endosomal compartments and plasma membrane. Knockdown of DDT and MIF in PANC-1 cells cooperatively inhibited ERK1/2 and AKT phosphorylation, increased p53 expression, and reduced cell proliferation, invasion and tumor formation. These effects were rescued by the re-expression of MIF or DDT, but not by the forced expression of the tautomerase-deficient mutants of DDT and MIF, P1G-DDT and P1G-MIF. Finally, we observed that 4-iodo-6-phenylpyrimidine (4-IPP), a covalent tautomerase inhibitor of both DDT and MIF, attenuated PANC-1 cell proliferation and colony formation in vitro and tumor growth in vivo. Thus, targeting the tautomerase sites of both MIF and DDT may offer more efficient therapeutic benefits to PDAC patients.

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Targeting MIF in Cancer: Therapeutic Strategies, Current Developments, and Future Opportunities

O’Reilly

Doroudian

Mawhinney

et al. 2016

Medicinal Research Reviews

115

126

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Strong evidence has been presented linking chronic inflammation to the onset and pathogenesis of cancer. The multifunctional pro-inflammatory protein macrophage migration inhibitory factor (MIF) occupies a central role in the inflammatory pathway and has been implicated in the tumorigenesis, angiogenesis, and metastasis of many cancer phenotypes. This review highlights the current state of the art, which presents MIF, and the second member of the MIF structural superfamily, D-DT (MIF2), as significant mediators in the inflammatory-cancer axis. Although the mechanism by which MIF asserts its biological activity has yet to be fully understood, it has become clear in recent years that for certain phenotypes of cancer, MIF represents a valid therapeutic target. Current research efforts have focused on small molecule approaches that target MIF's unique tautomerase active site and neutralization of MIF with anti-MIF antibodies. These approaches have yielded promising results in a number of preclinical murine cancer models and have helped to increase our understanding of MIF biological activity. More recently, MIF's involvement in a number of key protein-protein interactions, such as with CD74 and HSP90, has been highlighted and provides a novel platform for the development of anti-MIF chemotherapeutic strategies in the future.

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Negative Regulation of AMP-activated Protein Kinase (AMPK) Activity by Macrophage Migration Inhibitory Factor (MIF) Family Members in Non-small Cell Lung Carcinomas

Cited by 39 publications

References 46 publications

Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

D‐dopachrome tautomerase is over‐expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth

Targeting MIF in Cancer: Therapeutic Strategies, Current Developments, and Future Opportunities

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