Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1

Forti, Fábio Luís; Armelin, Hugo A.

doi:10.1677/erc-07-0154

Cited by 15 publications

(13 citation statements)

References 26 publications

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“…In Y1 cells, the cell cycle is partially deregulated by two independent oncogenic lesions. First, constitutively high levels of K-Ras-GTP lead to the elevated activity of the phosphoinositide-3-kinase/Akt pathway (26,29,30); second, cyclins D1 and E are simultaneously induced instead of being induced sequentially (Supplementary Data, Fig. S5), meaning that progression through G 1 lies under the exclusive control of the signaling pathway: ERK1/2 !…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 2 Restrains Ras-Driven Proliferation of Malignant Cells by Triggering RhoA-Mediated Senescence

et al. 2008

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Fibroblast growth factor 2 (FGF2) is considered to be a bona fide oncogenic factor, although results from our group and others call this into question. Here, we report that exogenous recombinant FGF2 irreversibly inhibits proliferation by inducing senescence in Ras-dependent malignant mouse cells, but not in immortalized nontumorigenic cell lines. We report the following findings in K-Ras-dependent malignant Y1 adrenocortical cells and H-Ras V12-transformed BALB-3T3 fibroblasts: (a) FGF2 inhibits clonal growth and tumor onset in nude and immunocompetent BALB/c mice, (b) FGF2 irreversibly blocks the cell cycle, and (c) FGF2 induces the senescence-associated B-galactosidase with no accompanying signs of apoptosis or necrosis. The tyrosine kinase inhibitor PD173074 completely protected malignant cells from FGF2. In Y1 adrenal cells, reducing the constitutively high levels of K-Ras-GTP using the dominant-negative RasN17 mutant made cells resistant to FGF2 cytotoxicity. In addition, transfection of the dominant-negative RhoA-N19 into either Y1 or 3T3-B61 malignant cell lines yielded stable clonal transfectants that were unable to activate RhoA and were resistant to the FGF2 stress response. We conclude that in Rasdependent malignant cells, FGF2 interacts with its cognate receptors to trigger a senescence-like process involving RhoA-GTP. Surprisingly, attempts to select FGF2-resistant cells from the Y1 and 3T3-B61 cell lines yielded only rare clones that (a) had lost the overexpressed ras oncogene, (b) were dependent on FGF2 for proliferation, and (c) were poorly tumorigenic. Thus, FGF2 exerted a strong negative selection that Rasdependent malignant cells could rarely overcome. [Cancer Res 2008;68(15):6215-23]

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Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 2 Restrains Ras-Driven Proliferation of Malignant Cells by Triggering RhoA-Mediated Senescence

et al. 2008

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“…This finding is in line with two in vitro studies which found RhoA negatively regulated AKT phosphorylation and decreased cyclin D1 levels in endothelial cells and K-Ras-driven adrenocortical cancer cell lines. 95, 96 Another recent study of a murine colon cancer model induced by mutant APC found that simultaneous expression of dominant negative RhoA resulted in larger and more frequent adenomas and decreased survival. 97 Perhaps more intriguing, conditional gene deletion of either RhoA or RhoC alone did not suppress K-Ras G12D induced lung adenoma initiation.…”

Section: Rho Gtpases With Potential Tumor Suppressing Rolesmentioning

confidence: 99%

Rho GTPases: Anti- or pro-neoplastic targets?

et al. 2016

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Rho GTPases are critical signal transducers of multiple pathways. They have been proposed to be useful anti-neoplastic targets for over two decades, especially in Ras-driven cancers. Until recently, however, few in vivo studies had been carried out to test this premise. Several recent mouse model studies have verified that Rac1, RhoA, and some of their effector proteins such as PAK and ROCK, are likely anti-cancer targets for treating K-Ras-driven tumors. Other seemingly contradictory studies have suggested that at least in certain instances inhibition of individual Rho GTPases may paradoxically result in pro-neoplastic effects. Significantly, both RhoA GTPase gain- and loss-of-function mutations have been discovered in primary leukemia/lymphoma and gastric cancer by human cancer genome sequencing efforts, suggesting both pro- and anti-neoplastic roles. In this review we summarize and integrate these unexpected findings and discuss the mechanistic implications in the design and application of Rho GTPase targeting strategies in future cancer therapies.

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“…The plasmids were packaged into retroviral particles suspended in the viral vector supernatant ([10 6 c.f.u.) and used to transduce or infect HeLa cells in the presence of 4 lg/mL polybrene (Sigma) for 24 h. The selection of infected HeLa cells (clones) was performed in culture medium containing the G418 antibiotic (400 lg/mL) because the pCM vector contains the neomycin resistance gene (adapted from [19]). Six HeLa-Rac1-N17 and six HeLa-Rac1-V12 clones were isolated and tested by (a) examining Rac1 activity by measuring basal levels of Rac1-GTP in pull-down assays, (b) determining migration ability in scratch wound healing assays in the presence or absence of serum, and (c) performing clonogenic assays for checking survival (results not shown).…”

Section: Cell Culturementioning

confidence: 99%

Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation

et al. 2015

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Rac1 GTPase controls essential cellular functions related to the cytoskeleton, such as motility and adhesion. Rac1 is overexpressed in many tumor cells, including breast cancers, where it is also involved in the proliferation and checkpoint control necessary for the cell's recovery after exposure to ionizing radiation. However, its role in DNA damage and repair remains obscure in other tumor cells and under different genotoxic conditions. Here, we compare HeLa cells with mutants exogenously expressing a dominant-negative Rac1 (HeLa-Rac1-N17) by their responses to DNA damage induced by gamma or UV radiation. In HeLa cells, these treatments led to increased levels of active Rac1 (Rac1-GTP) and of stress fibers, with a diminished ability to migrate compared to untreated cells. However, the reduction of Rac1-GTP in Rac1-N17-deficient clones resulted in much higher levels of polymerized stress fibers accompanied by a strong impairment of cell migration, even after both radiation treatments. With regard to proliferation and genomic stability, dominant-negative Rac1 cells were more sensitive to gamma and UV radiation, exhibiting reduced proliferation and survival consistent with increased DNA damage and delayed or reduced DNA repair observed in this Rac1-deficient clone. The DNA damage response, as indicated by pH2AX and pChk1 levels, was increased in HeLa cells but was not effectively triggered in the Rac1-N17 clone after radiation treatment, which is likely the main cause of DNA damage accumulation. These data suggest that Rac1 GTPase plays an important role in signaling and contributes to the sensitivity of cervical cancer cells under UV or gamma radiation treatments.

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Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1

Cited by 15 publications

References 26 publications

Fibroblast Growth Factor 2 Restrains Ras-Driven Proliferation of Malignant Cells by Triggering RhoA-Mediated Senescence

Fibroblast Growth Factor 2 Restrains Ras-Driven Proliferation of Malignant Cells by Triggering RhoA-Mediated Senescence

Rho GTPases: Anti- or pro-neoplastic targets?

Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation

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