Rac1-Dependent Lamellipodial Motility in Prostate Cancer PC-3 Cells Revealed by Optogenetic Control of Rac1 Activity

Kato, Takuma; Kawai, Kensuke; Egami, Youhei; Kakehi, Yoshiyuki; Araki, Nobuhito

doi:10.1371/journal.pone.0097749

Cited by 38 publications

(42 citation statements)

References 35 publications

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“…Studies have shown that the overexpression of Rac1 in tissue samples from patients with prostate cancer is associated with poor patient prognosis 32 . Studies have also shown that activation of Rac1 via the PI3K/AKT pathway is essential for the induction of migration in PC3 cells 33 . It has also been observed that inhibition of active form of Rac1 (GTP bound Rac1) causes antimigratory effects in prostate cancer cells 34 .…”

Section: Discussionmentioning

confidence: 99%

Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells

et al. 2020

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Background Mammalian target of rapamycin (mTOR) is a downstream substrate activated by PI3K/AKT pathway and it is essential for cell migration. It exists as two complexes: mTORC1 and mTORC2. mTORC1 is known to be regulated by active AKT, but the activation of mTORC2 is poorly understood. In this study, we investigated the roles and differential activation of the two mTOR complexes during cell migration in prostate cancer cells. Methods We used small interfering RNA to silence the expression of Rac1 and the main components of mTOR complexes (regulatory associated protein of mTOR [RAPTOR] and rapamycin‐insensitive companion of mTOR [RICTOR]) in LNCaP, DU145, and PC3 prostate cancer cell lines. We performed transwell migration assay to evaluate the migratory capability of the cells, and Western blot analysis to study the activation levels of mTOR complexes. Results Specific knockdown of RAPTOR and RICTOR caused a decrease of cell migration, suggesting their essential role in prostate cancer cell movement. Furthermore, epidermal growth factor (EGF) treatments induced the activation of both the mTOR complexes. Lack of Rac1 activity in prostate cancer cells blocked EGF‐induced activation of mTORC2, but had no effect on mTORC1 activation. Furthermore, the overexpression of constitutively active Rac1 resulted in significant increase in cell migration and activation of mTORC2 in PC3 cells, but had no effect on mTORC1 activation. Active Rac1 was localized in the plasma membrane and was found to be in a protein complex, with RICTOR, but not RAPTOR. Conclusion We suggest that EGF‐induced activation of Rac1 causes the activation of mTORC2 via RICTOR. This mechanism plays a critical role in prostate cancer cell migration.

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Section: Discussionmentioning

confidence: 99%

Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells

et al. 2020

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“…Overexpression of Rac1 occurs in several different types of tumors including breast (16,17), colon (18), bladder (19), and gastric cancer (20,21). Rac1 overexpression was observed in metastatic gastric (21), breast (15), prostate (22), bladder upper urinary tract cancer (19). Rac1 promoted prostate cancer progression and recurrence upon activation by VAV3, a GEF for Rac1 activation (14).…”

Section: Introductionmentioning

confidence: 99%

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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“…Similarly, I predict that the effect of fibrinogen on WAVE complex‐1 formation is abolished in the absence of SYK–PI3K interaction and the WAVE complex‐1 does not form in the absence of this interaction, which is in agreement with Kato et al . and Weering et al . , who show that inhibiting PI3K inhibits lamellipodia extension.…”

Section: Discussionmentioning

confidence: 88%

Central role of PI3K–SYK interaction in fibrinogen‐induced lamellipodia and filopodia formation in platelets

Singh

2016

FEBS Open Bio

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The WAVE complex‐1, a complex of WAVE , Abi1, NAP 1, PIR 121, HSPC 300, Rac GTP and Arp2/3 proteins, and WASP complex‐1, a complex of WASP , Cdc42, PIP 2, and Arp2/3 proteins, are involved in lamellipodia and filopodia formation, respectively. It is known that the two complexes have opposite dynamics. Furthermore, Rac has two guanine nucleotide exchange factors, Vav and Sos, whose role in activating Rac is not well understood. In this work, by the construction of signaling network, analysis, and mathematical modeling, I show that Sos generates a pulse of WAVE complex‐1, decreasing the response time of WAVE complex‐1 formation upon the stimulation of platelets by fibrinogen. Furthermore, I also show that the dynamics of WAVE and WASP complexes depends on PI 3K– SYK interaction. In the absence of this interaction, the WAVE complex‐1 does not form and the WASP complex‐1 remains at the initial, sustained level. Thus, I show the significance of the two protein/protein complexes: Sos and PI 3K– SYK interaction, in fibrinogen‐induced lamellipodia and filopodia formation in platelets.

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Rac1-Dependent Lamellipodial Motility in Prostate Cancer PC-3 Cells Revealed by Optogenetic Control of Rac1 Activity

Cited by 38 publications

References 35 publications

Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells

Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells

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

Central role of PI3K–SYK interaction in fibrinogen‐induced lamellipodia and filopodia formation in platelets

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