TC21 promotes cell motility and metastasis by regulating the expression of E-cadherin and N-cadherin in hepatocellular carcinoma

Luo, Hanwen; Xia, Hao; Ge, Chao; Zhao, Fangyu; Zhu, Ming; Chen, Taoyang; Yao, Ming; He, Xianghuo; Li, Jinjun

doi:10.3892/ijo_00000736

Cited by 24 publications

(27 citation statements)

References 21 publications

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“…Additionally, Cdc42 inhibition by AZA197 resulted in increased apoptosis in vivo and in vitro . Moreover, colon cancer cells overexpressing PAK1 have higher migration rates, whereas down-regulation of PAK1 significantly reduces cell migration [17]. This is in line with our findings of reduced SW620 cancer cell migration following AZA197 treatment.…”

Section: Discussionsupporting

confidence: 89%

“…Overexpression of PAK1 has been detected in colorectal cancer and PAK1 expression closely correlated with the aggressive progression of colorectal cancer [17,43]. A recent study showed that PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…GTP-bound Cdc42 can interact with multiple downstream signaling pathways, including activation of p21-activated protein kinase (PAK), which is involved in invasion, migration and oncogenic transformation [15,16]. Additionally, PAK1 expression is significantly increased in colorectal cancer and closely correlates with aggressive disease progression [17]. Moreover, Cdc42 was found to be over-expressed with high incidence in colorectal cancer samples suggesting a potential role for Cdc42 in tumor development [18].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity

et al. 2013

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BackgroundRho GTPases play important roles in cytoskeleton organization, cell cycle progression and are key regulators of tumor progression. Strategies to modulate increased Rho GTPase activities during cancer progression could have therapeutic potential.MethodsWe report here the characterization of a Cdc42-selective small-molecule inhibitor AZA197 for the treatment of colon cancer that was developed based on structural information known from previously developed compounds affecting Rho GTPase activation. We investigated the effects of AZA197 treatment on RhoA, Rac1 and Cdc42 activities and associated molecular mechanisms in colon cancer cells in vitro. Therapeutic effects of AZA197 were examined in vivo using a xenograft mouse model of SW620 human colon cancer cells. After treatment, tumors were excised and processed for Ki-67 staining, TUNEL assays and Western blotting to evaluate proliferative and apoptotic effects induced by AZA197.ResultsIn SW620 and HT-29 human colon cancer cells, AZA197 demonstrated selectivity for Cdc42 without inhibition of Rac1 or RhoA GTPases from the same family. AZA197 suppressed colon cancer cell proliferation, cell migration and invasion and increased apoptosis associated with down-regulation of the PAK1 and ERK signaling pathways in vitro. Furthermore, systemic AZA197 treatment reduced tumor growth in vivo and significantly increased mouse survival in SW620 tumor xenografts. Ki-67 staining and tissue TUNEL assays showed that both inhibition of cell proliferation and induction of apoptosis associated with reduced PAK/ERK activation contributed to the AZA197-induced therapeutic effects in vivo.ConclusionsThese data indicate the therapeutic potential of the small-molecule inhibitor AZA197 based on targeting Cdc42 GTPase activity to modulate colorectal cancer growth.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity

et al. 2013

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“…Several studies including our own link PAK1 to ERK1/2 [5], [44], [50]. Loss of PAK1 results in downregulation of ERK activity with negative effects on cell motility/migration [29], [78], and proliferation [79]. Furthermore, PAK1 activation induced by adhesion to matrix proteins activates the MAPK signaling cascade and is thought to be a convergence site between integrins and growth factor signaling [80], [81].…”

Section: Discussionmentioning

confidence: 89%

“…Furthermore, one or more group I PAK members regulates endothelial cell migration mediated by Ang-1, and its activation is necessary for restoring vascular permeability as the last step in the angiogenesis process that prepares nascent vessels for perfusion [20], [21]. PAK1 is also a strong stimulator of proliferation and migration, leading to the aggressive behavior of human cancers [22]–[29]. All of the aforementioned studies have established a relationship between PAK1 function and angiogenesis in vitro, thereby predicting a role for PAK1 in angiogenesis in vivo .…”

Section: Introductionmentioning

confidence: 99%

Potential Compensation among Group I PAK Members in Hindlimb Ischemia and Wound Healing

et al. 2014

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PAKs are serine/threonine kinases that regulate cytoskeletal dynamics and cell migration. PAK1 is activated by binding to the small EF hand protein, CIB1, or to the Rho GTPases Rac1 or Cdc42. The role of PAK1 in angiogenesis was established based only on in vitro studies and its role in angiogenesis in vivo has never been examined. Here we tested the hypothesis that PAK1 is an essential regulator of ischemic neovascularization (arteriogenesis and angiogenesis) and wound healing using a global PAK1 knockout mouse. Neovascularization was assessed using unilateral hindlimb ischemia. We found that plantar perfusion, limb use and appearance were not significantly different between 6–8 week old PAK1−/− and PAK1+/+ mice throughout the 21-day period following hindlimb ischemia; however a slightly delayed healing was observed in 16 week old PAK1−/− mice. In addition, the wound healing rate, as assessed with an ear punch assay, was unchanged in PAK1−/− mice. Surprisingly, however, we observed a notable increase in PAK2 expression and phosphorylation in ischemic gastrocnemius tissue from PAK1−/− but not PAK1+/+ mice. Furthermore, we observed higher levels of activated ERK2, but not AKT, in ischemic and non-ischemic muscle of PAK1−/− mice upon hindlimb ischemic injury. A group I PAK inhibitor, IPA3, significantly inhibited endothelial cell sprouting from aortic rings in both PAK1−/− and PAK1+/+ mice, implying that PAK2 is a potential contributor to this process. Taken together, our data indicate that while PAK1 has the potential to contribute to neovascularization and wound healing, PAK2 may functionally compensate when PAK1 is deficient.

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The Role of R-Ras Proteins in Normal and Pathologic Migration and Morphologic Change

Weber¹,

Carroll²

2021

The American Journal of Pathology

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The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome (NS), a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular, and nervous systems. Consistent with the abnormalities seen in NS, a host of new studies have implicated R-Ras proteins in physiological and pathologic changes in cellular morphology, adhesion, and migration in the cardiovascular, immune, and nervous systems. These changes include regulating the migration and homing of mature and immature immune cells, vascular stabilization, clotting, and axonal and dendritic outgrowth during nervous system development. Dysregulated R-Ras signaling has also been linked to the pathogenesis of cardiovascular disease, intellectual disabilities, and human cancers. This review discusses the structure and regulation of R-Ras proteins and our current understanding of the signaling pathways that they regulate. It explores the phenotype of NS patients and their implications for the R-Ras subfamily functions. Next, it covers recent discoveries regarding physiological and pathologic R-Ras functions in key organ systems. Finally, it discusses how R-Ras signaling is dysregulated in cancers and mechanisms by which this may promote neoplasia.

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TC21 promotes cell motility and metastasis by regulating the expression of E-cadherin and N-cadherin in hepatocellular carcinoma

Cited by 24 publications

References 21 publications

Targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity

Targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity

Potential Compensation among Group I PAK Members in Hindlimb Ischemia and Wound Healing

The Role of R-Ras Proteins in Normal and Pathologic Migration and Morphologic Change

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