Rho GTPases RhoA and Rac1 Mediate Effects of Dietary Folate on Metastatic Potential of A549 Cancer Cells through the Control of Cofilin Phosphorylation

Oleinik, Natalia; Helke, Kristi L.; Kistner-Griffin, Emily; Krupenko, Natalia I.; Krupenko, Sergey A.

doi:10.1074/jbc.m114.569657

Cited by 46 publications

(47 citation statements)

References 63 publications

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“…Rac1 promoted colon cancer progression through promotion of cell proliferation, survival and migration (36). Rac1 expression is correlated with tumorigenesis, aggressiveness and treatment resistance in a number of cancers such as lung (37,38), breast cancer (39,40) and melanoma (23,41). These clinical investigations have shown the close correlation of Rac1 with human cancers.…”

Section: Discussionmentioning

confidence: 94%

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Feng

Shi

et al. 2015

International Journal of Oncology

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Abstract. Rac1 is a member of the Rho GTPase family. Rac1 activity is critical in regulating cytoskeleton organization and thus, modulates a diverse spectrum of cellular functions in normal and malignant cells. The aims of the present study were to investigate the expression pattern and clinical significance of Rac1, as well as the role of Rac1 in gastric cancer tumorigenesis and metastasis. The expression of Rac1 in human gastric cancer was explored by immunohistochemistry. The correlation of Rac1 expression with the clinicopathological characteristics and the survival of patients were analyzed by Pearson's Chi-square and KaplanMeier analyses, respectively. Rac1 overexpression cell model was used to examine in vitro and in vivo effects of Rac1 in cell growth, migration and invasion. Rac1 was highly expressed in gastric cancer tissues and correlated with differentiation, local invasion, lymph node metastasis and Lauren's classification. Rac1 expression in gastric cancer predicted shorter survival. Overexpression of Rac1 in gastric cancer cells dramatically induced Rac1 activation and rendered a more aggressive phenotype such as increased cell growth and migration/invasion in vitro and in vivo. Inhibiting Rac1 activity by specific inhibitor abrogated the effects of Rac1 on the malignant phenotype. Our clinical findings demonstrated that Rac1 was well correlated with aggressiveness and a negative prognostic factor. In addition, our data on experimental cell models supported the fundamental role of Rac1 in gastric cancer. Given its pivotal role in gastric tumorigenesis and progression, Rac1 can serve as a promising therapeutic target for gastric cancer.

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Section: Discussionmentioning

confidence: 94%

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Feng

Shi

et al. 2015

International Journal of Oncology

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“…Studies from this laboratory have demonstrated that folate regulates motility of A549 human lung cancer cells through an effect on cofilin-dependent actin dynamics (21). Furthermore, the cofilin-actin axis underlies the inhibition of metastasis and increased survival associated with dietary folate restriction in a lung cancer model in severe combined immunodeficient mice (22). These results are in apparent conflict with findings of an inhibitory effect of increased folate on invasiveness of HCT116 human colon cancer cells via the activation of sonic hedgehog pathways (23).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype

Ashkavand

O’Flanagan

Hennig

et al. 2017

Molecular Cancer Research

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Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration and survival in many cell types. Here the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: non-invasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wntliver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quantitate 41 major metabolites in cells grown in folate-free medium versus standard medium. Each cell line demonstrated metabolic reprogramming when grown in folate-free medium. In E-Wnt, M-Wnt and metM-Wntliver cells 12, 29, and 25 metabolites, respectively, were significantly different (p<0.05 and at least 1.5-fold change). The levels of eight metabolites (aspartate, ATP, creatine, creatine phosphate, formate, serine, taurine and β-alanine) were changed in each folate-restricted cell line. Increased glucose, decreased lactate, and inhibition of glycolysis, cellular proliferation, migration and invasion occurred in M-Wnt and metM-Wntliver cells (but not E-Wnt cells) grown in folate-free versus standard medium. These effects were accompanied by altered levels of several folate-metabolizing enzymes, indicating that the observed metabolic reprogramming may result from both decreased folate availability and altered folate metabolism. These findings reveal that folate restriction results in metabolic and bioenergetic changes and a less aggressive cancer cell phenotype. Implications Metabolic reprogramming driven by folate restriction represents a therapeutic target for reducing the burden of breast cancer.

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“…Lim domain kinases (LIMKs) 4 and testis-specific protein kinases (TESKs) are responsible for the phosphorylation of Cofilin, whereas slingshot (SSH) family protein phosphatases and pyridoxal phosphatase (PDXP) catalyze the dephosphorylation reaction (16 -20). These kinases and phosphatases are also regulated by their phosphorylation or localization in cytoplasm to maintain the level of Cofilin phosphorylation in response to extracellular stimuli (21)(22)(23).…”

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confidence: 99%

Trp-Asp (WD) Repeat Domain 1 Is Essential for Mouse Peri-implantation Development and Regulates Cofilin Phosphorylation

Xiao

Wan

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangTrp-Asp (WD) repeat domain 1 (WDR1) is a highly conserved actin-binding protein across all eukaryotes and is involved in numerous actin-based processes by accelerating Cofilin severing actin filament. However, the function and the mechanism of WDR1 in mammalian early development are still largely unclear. We now report that WDR1 is essential for mouse periimplantation development and regulates Cofilin phosphorylation in mouse cells. The disruption of maternal WDR1 does not obviously affect ovulation and female fertility. However, depletion of zygotic WDR1 results in embryonic lethality at the periimplantation stage. In WDR1 knock-out cells, we found that WDR1 regulates Cofilin phosphorylation. Interestingly, WDR1 is overdosed to regulate Cofilin phosphorylation in mouse cells. Furthermore, we showed that WDR1 interacts with Lim domain kinase 1 (LIMK1), a well known phosphorylation kinase of Cofilin. Altogether, our results provide new insights into the role and mechanism of WDR1 in physiological conditions.The actin cytoskeleton is a highly dynamic structure that regulates cell motility, adhesion, division, and growth and has a fundamental function in embryonic development (1-3). In physiological conditions, actin filaments are continually assembled and disassembled in response to varied cellular activities (4, 5). The dynamics of F-actin is well orchestrated by a large number of actin-binding proteins (5, 6). Actin-depolymerizing factor Cofilin plays critical roles in the modulation of actin cytoskeleton dynamics (7). In vitro, Cofilin severs actin filament at low concentrations, whereas it fully decorates actin filaments and suppresses the severing activity at high concentrations (8, 9). In addition, Cofilin severing F-actin is not explained well for how the filaments of actin cytoskeleton can be rapidly disassembled in physiological conditions (4). Thus, the function of Cofilin in actin dynamics depends not only on its relative concentration to actin, but also on other regulatory proteins in vivo. Dysfunction of these regulating proteins results in aberrant actin cytoskeleton in various cellular and developmental processes (10 -12).Cofilin directly binds with actin to function as a regulator of the actin dynamics (13). However, the phosphorylation of Cofilin at Ser-3 blocks its binding site to actin (14, 15). Thus, the activity of Cofilin is controlled by phosphorylation and dephosphorylation processes, which are regulated by cascade reactions of several protein kinases and phosphatases. Lim domain kinases (LIMKs) 4 and testis-specific protein kinases (TESKs) are responsible for the phosphorylation of Cofilin, whereas slingshot (SSH) family protein phosphatases and pyridoxal phosphatase (PDXP) catalyze the dephosphorylation reaction (16 -20). These kinases and phosphatases are also regulated by their phosphorylation or localization in cytoplasm to maintain the level of Cofilin phosphorylation in response to extracellular stimuli (21-23).The activity of Cofilin on actin disassembly is gr...

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Rho GTPases RhoA and Rac1 Mediate Effects of Dietary Folate on Metastatic Potential of A549 Cancer Cells through the Control of Cofilin Phosphorylation

Cited by 46 publications

References 63 publications

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype

Trp-Asp (WD) Repeat Domain 1 Is Essential for Mouse Peri-implantation Development and Regulates Cofilin Phosphorylation

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