Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632

Takamura, Masaaki; Sakamoto, Michiie; Genda, Takuya; Ichida, Takafumi; Asakura, Hitoshi; Hirohashi, Setsuo

doi:10.1053/jhep.2001.22652

Cited by 114 publications

(92 citation statements)

References 16 publications

(28 reference statements)

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“…The results of the present study revealed that afzelin inhibited the protein expression levels of MRCKα and ROCK1, clarifying that downregulation of LIMK1 by afzelin is due to its inhibitory effect on MRCKα and ROCK1, upstream in its signaling pathway. Previous studies have demonstrated that ROCK inhibitors appear to reduce the invasive ability of tumor cells in vitro and prevent the dissemination of tumor cells in vivo in different types of cancer, particularly in prostate cancer (10,(13)(14)(15)(16)(17)38). Furthermore, LIMK1, MRCKα and ROCK1 are proteins of interest in the development of novel cancer therapies due to their involvement in regulating actin organization (7) and, in combination with other proteins, maintaining the tight regulation of normal cell growth and differentiation (8,9).…”

Section: Discussionmentioning

confidence: 99%

“…The Rho GTPase myotonic dystrophy kinase-related Cdc42-binding kinase α (MRCKα), Rho-associated coiled-coil containing protein kinase (ROCK)1 and ROCK2 are responsible for the activation of LIMK1 (9,12). Previous studies have demonstrated the ability of ROCK inhibitors to reduce the invasive ability of tumor cells in vitro and prevent the spread of tumor cells in vivo, including melanoma and fibrosarcoma cells, as well as liver, breast, lung and prostate cancer tumor cells (13)(14)(15)(16)(17) Thus, inhibitors of LIMK1, MRCKα and ROCK1/2 are considered to restore normal cell proliferation and provide a key strategy for cancer treatment (18). Therefore, the aim of the present study was to evaluate the in vitro anti-prostate cancer activity of afzelin and its effect on prostate cancer-associated kinases.…”

Section: Introductionmentioning

confidence: 99%

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Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1

et al. 2015

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Abstract. Prostate cancer presents high occurrence worldwide. Medicinal plants are a major source of novel and potentially therapeutic molecules; therefore, the aim of the present study was to investigate the possible anti-prostate cancer activity of afzelin, a flavonol glycoside that was previously isolated from Nymphaea odorata. The effect of afzelin on the proliferation of androgen-sensitive LNCaP and androgen-independent PC-3 cells was evaluated by performing a water soluble tetrazolium salt-1 assay. In addition, the effect of afzelin on the cell cycle of the LNCaP and PC-3 prostate cancer cell lines was evaluated. Western blot analysis was performed to evaluate the effect of afzelin on the kinases responsible for the regulation of actin organization. Afzelin was identified to inhibit the proliferation of LNCaP and PC3 cells, and block the cell cycle in the G 0 phase. The anticancer activity of afzelin in these cells was determined to be due to inhibition of LIM domain kinase 1 expression. Thus, the in vitro efficacy of afzelin against prostate cancer is promising; however, additional studies on different animal models are required to substantiate its anticancer potential. IntroductionProstate cancer is the second most frequently diagnosed type of cancer and the sixth most common cause of cancer-associated mortality in males, worldwide (1). The typical treatment strategies of chemotherapy and radiotherapy have not provided significant survival benefits for patients with advanced prostate cancer, and the majority of available strategies are only palliative (2). Therefore, there is requirement for the prompt identification of novel molecules to treat the increasing number of prostate cancer cases, particularly cases that are resistant to current chemotherapeutic agents (3,4).Afzelin is a flavonol glycoside found in Nymphaea odorata, which has been identified to inhibit the growth of breast cancer cells by stimulating apoptosis (5). In addition, afzelin has been demonstrated to scavenge superoxide anion radicals in RAW264.7 cells (6). The structure of this compound is shown in Fig. 1.In eukaryotic cells, the actin cytoskeleton is essential for mediating various biological functions, including providing the structural framework of the cell, and driving cellular motility and division. In particular, dynamic reorganization of the actomyosin cytoskeleton and remodelling of the extracellular matrix drive the multistep process of tumor cell metastasis. Tumor cells are able to cross tissue boundaries into the blood and lymphatic systems and migrate to distal regions of the body. Therefore, cancer therapy has recently focused on gaining a comprehensive understanding of the biological processes that regulate actin organization (7).Rho GTPase family proteins are key regulators of the actin cytoskeleton and, with the aid of various target proteins, maintain the tight regulation of normal cell growth and differentiation (8-11). Eukaryotic cells exhibit a predisposition to rapid and uncontrollable growth following genomic a...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1

et al. 2015

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“…Along with its partner protein Max, c-Myc regulates an estimated 10% to 15% of genes in the human genome, and globally reprograms cells and drives proliferation (1)(2)(3). Aberrant regulation and overexpression of c-Myc are observed in most tumor types, and the c-Myc signaling is believed to play a critical role in oncogenesis (4)(5)(6)(7). A large body of studies have shown that c-Myc is pathologically amplified and/or overexpressed in breast cancers (8,9), particularly in late-stage tumors (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, cMyc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosome proteins. However, how to elucidate the deregulation of rRNAs and ribosome proteins driven by c-Myc in cancer remains a significant challenge and thus warrants close investigation. In this report, a crucial role for the HSPC111 (NOP16) multiprotein complex in governing ribosomal biogenesis and tumor growth was determined. It was discovered that enhanced HSPC111 expression paralleled the upregulation of c-Myc and was directly regulated by c-Myc in breast cancer cells. Knockdown of HSPC111 dramatically reduced the occurrence of tumorigenesis in vivo, and largely restrained tumor cell growth in vitro and in vivo. In stark contrast, HSPC111 overexpression significantly promoted tumor cell growth. Biochemically, it was demonstrated that RNA 3 0 -phosphate cyclase (RTCD1/RTCA) interacted with HSPC111, and RTCD1 was involved in the HSPC111 multiprotein complex in regulating rRNA production and ribosomal biogenesis. Moreover, HSPC111 and RTCD1 synergistically modulated cell growth and cellular size through commanding rRNA synthesis and ribosome assembly coupled to protein production. Finally, overall survival analysis revealed that concomitant upregulation of HSPC111 and RTCD1 correlated with the worst prognosis in a breast cancer cohort.Implications: Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression. Mol Cancer Res; 12(4); 583-94. Ó2014 AACR. IntroductionBreast cancer is by far the most common cancer among women and the leading cause of cancer-related deaths worldwide. The primary tumor and metastases to distant organs often cause significant morbidity and mortality. Numerous studies suggest that the oncogene c-Myc plays a crucial role in the development and progression of breast cancer. Along with its partner protein Max, c-Myc regulates an estimated 10% to 15% of genes in the human genome, and globally reprograms cells and drives proliferation (1-3). Aberrant regulation and overexpression of c-Myc are observed in most tumor types,

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“…The link between transcription with transformation, cell invasion, and metastasis is particularly interesting. Ever since it was shown that overexpression of either RhoA, Rac1, or Cdc42 transforms and promotes the metastatic phenotype of cultured 3T3 fibroblasts (Ballestero et al, 1991;Perona et al, 1993;del Peso et al, 1997), many studies have described the physiological relevance of Rho signaling and overexpression in human tumors (Clark et al, 2000;Mira et al, 2000;Van Golen et al, 2000a,b;Abraham et al, 2001;Kamai et al, 2001;Keely, 2001;Matsumoto et al, 2001;Takamura et al, 2001;Takemoto et al, 2001). Overexpression of Rho GTPases occurs in many types of human tumors, and RhoA and Rac2 constitute early markers for tumor progression of head and neck squamous cell cancer (Abraham et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

Benitah¹,

Valerón²,

Rui

et al. 2003

MBoC

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The involvement of Rho GTPases in signal transduction pathways leading to transcription activation is one of the major roles of this family of GTPases. Thus, the identification of transcription factors regulated by Rho GTPases and the understanding of the mechanisms of their activation and its biological outcome are of great interest. Here, we provide evidence that Rho GTPases modulate Stat5a, a transcription factor of the family of signal transducers and activators of transcription. RhoA triggers tyrosine phosphorylation (Y696) of Stat5a via a JAK2-dependent mechanism and promotes DNA-binding activity of Stat5a. Tyrosine phosphorylation of Stat5a is also stimulated physiologically by lysophosphatidic acid (LPA) in a Rho-dependent manner. Simultaneously, RhoA reduces serine phosphorylation of Stat5a at both serine residues S726 and S780, resulting in a further increase of activity as defined by mutagenesis experiments. Furthermore, serine dephosphorylation of Stat5a by RhoA does not take place by down-modulation of either JNK1, MEK1, or p38 MAP kinases, as determined by transfection experiments or chemical inhibition of both MEK1, p38, and JNK serine kinases. Thus, RhoA regulates Stat5a via tyrosine phosphorylation and via a yet to be determined novel down-modulating pathway that involves serine dephosphorylation. Finally, we provide evidence for a role of Stat5a in RhoA-induced epithelial-to-mesenchymal transition with concomitant increase in vimentin expression, E-cadherin down-regulation, and cell motility

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Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632

Cited by 114 publications

References 16 publications

Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1

Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

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