Effects of the farnesyltransferase inhibitor UCF-1C/manumycin on growth and p21-ras post-translational processing in NIH3T3 cells

Servais, Patricia; Gulbis, Béatrice; Fokan, Dominique; Galand, Paul

doi:10.1002/(sici)1097-0215(19980518)76:4<601::aid-ijc25>3.0.co;2-8

Cited by 12 publications

(6 citation statements)

References 19 publications

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“…RhoB-F, farnesylated RhoB; RhoB-G, geranylgeranylated RhoB. 5 Pooling our data in this paper, our unpublished data, and the data by Selleri et al phosphorylation by manumycin. This suggested that NO is not absolutely required for DNA DSBs but contributed to DSBs.…”

Section: Discussionmentioning

confidence: 57%

“…ROS generation induced by FTIs may be a common phenomenon because this has been observed for five different FTIs in eight solid tumor cell lines and three leukemia cell lines (20). 5 Inhibiting expression of farnesyltransferase by targeting FNTB transcription with siRNA was not sufficient to induce ROS production. Therefore, the ability of FTIs to induce ROS was probably not a direct result of farnesyltransferase inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…However, the antineoplastic activity of FTIs also results, at least in part, from inhibition of the farnesylation of proteins other than Ras (3,4). More than 10 uncharacterized isoprenylated proteins are affected by FTIs (5). Among the known farnesylated proteins other than Ras, lamins A and B, Rap2, RhoB and RhoE, and inositol triphosphate 5-phosphatase type I may be relevant in intracellular signaling and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Farnesyltransferase Inhibitors Induce DNA Damage via Reactive Oxygen Species in Human Cancer Cells

Pan

She

Xu³

et al. 2005

Cancer Research

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Farnesyltransferase inhibitors (FTIs) possess antitumor activity. Based on recent findings, we hypothesized that FTIs induce reactive oxygen species (ROS) that damage DNA, leading to DNA damage responses. To test this hypothesis, we investigated the effects of FTIs on the generation of ROS, DNA double-strand breaks (DSB), DNA damage responses, and RhoB, and the effects of quenching ROS on these FTI effects. We evaluated four FTIs in human cancer cell lines of different tissue origins. We found that FTIs induced ROS and DSBs. Suppressing expression of the B-subunit of farnesyltransferase with siRNA did not induce ROS, but slightly attenuated the ROS induced by FTIs. N-acetyl-L-cysteine (NAC), but not caspase inhibitors, blocked FTI-induced DSBs, suggesting that the DSBs were caused by ROS and did not result from apoptosis. The DSBs led to DNA damage responses. H2AX became phosphorylated and formed nuclear foci. The DNAdamage-sensing molecules involved were probably ataxiatelangiectasia mutated protein (ATM) and DNA-dependent protein kinase (DNA-PK) but not ATM-and Rad3-related protein (ATR). Key components of the homologous recombination and nonhomologous end joining repair pathways (DNA-PK, BRCA1, and NBS1) underwent phosphorylation and formed nuclear foci. RhoB, a mediator of the antineoplastic effect of FTIs and a protein inducible by DNA damage, was increased by FTIs. This increase was blocked by NAC. We concluded that FTIs induced oxidative DNA damage by inducing ROS and initiated DNA damage responses, including RhoB induction, and there was a complex relationship among FTIs, farnesyltransferase, ROS, and RhoB. Our data also imply that inhibitors of DNA repair may accentuate the clinical efficacy of FTIs. (Cancer Res 2005; 65(9): 3671-81)

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Farnesyltransferase Inhibitors Induce DNA Damage via Reactive Oxygen Species in Human Cancer Cells

Pan

She

Xu³

et al. 2005

Cancer Research

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“…27 Although Man A and other farnesyl protein transferase inhibitors exerted growth inhibitory activity in various cancer cells, the mechanisms by which they exhibited their antiproliferative effect was not directly considered through blocking of ras function. 28, 29 As Man A also contained sulfhydryl (–SH)-reactive, α , β -unsaturated ketones in its structure, we explored whether antiproliferative actions of Man A are mediated through induction of cytoplasmic vacuolation death similar to 15d-PGJ2. 24 Here, we characterized the potential tumoricidal function of Man A in the treatment of TNBC by examining its effects both in vitro cell cultures and in vivo xenograft models.…”

mentioning

confidence: 99%

Manumycin A inhibits triple-negative breast cancer growth through LC3-mediated cytoplasmic vacuolation death

et al. 2013

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Therapy resistance can be attributed to acquisition of anti-apoptotic mechanisms by the cancer cells. Therefore, developing approaches that trigger non-apoptotic cell death in cancer cells to compensate for apoptosis resistance will help to treat cancer effectively. Triple-negative breast cancers (TNBC) are among the most aggressive and therapy resistant to breast tumors. Here we report that manumycin A (Man A), an inhibitor of farnesyl protein transferase, reduces cancer cell viability through induction of non-apoptotic, non-autophagic cytoplasmic vacuolation death in TNBC cells. Man A persistently induced cytoplasmic vacuolation and cell death through the expression of microtubule-associated protein 1 light chain 3 (LC3) and p62 proteins along with endoplasmic reticulum (ER) stress markers, Bip and CHOP, and accumulation of ubiquitinated proteins. As inhibitors of apoptosis and autophagy failed to block cytoplasmic vacuolation and its associated protein expression or cell death, it appears that these processes are not involved in the death induced by Man A. Ability of thiol antioxidant, NAC in blocking Man A-induced vacuolation, death and its related protein expression suggests that sulfhydryl homeostasis may be the target of Man A. Surprisingly, normal human mammary epithelial cells failed to undergo cytoplasmic vacuolation and cell death, and grew normally in presence of Man A. In conjunction with its in vitro effects, Man A also reduced tumor burden in vivo in xenograft models that showed extensive cytoplasmic vacuoles and condensed nuclei with remarkable increase in the vacuolation-associated protein expression together with increase of p21, p27, PTEN and decrease of pAkt. Interestingly, Man A-mediated upregulation of p21, p27 and PTEN and downregulation of pAkt and tumor growth suppression were also mimicked by LC3 knockdown in MDA-MB-231 cells. Overall, these results suggest novel therapeutic actions by Man A through the induction of non-apoptotic and non-autophagic cytoplasmic vacuolation death by probably affecting ER stress, LC3 and p62 pathways in TNBC but not in normal mammary epithelial cells.

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“…However, it is generally agreed that inhibition of p21 Ras farnesylation does not suppress mitogenic functions in Ras-transformed cells [38]. Moreover, it has recently been shown that growth inhibition by FTIs does not necessarily proceed from inhibition of p21 Ras prenylation, and that various Ras-unrelated proteins may be important targets for FTI treatment [2,19,29,39,40]. Even though it results in an altered subcellular distribution of p21 Ras [6], RPR-130401 is not able to block p21 Ras geranylgeranylation [24] in such a way that inhibition of p21 Ras farnesylation is not likely to account for the main effects of the drug.…”

Section: Discussionmentioning

confidence: 99%

The farnesyl transferase inhibitor RPR-130401 does not alter radiation susceptibility in human tumor cells with a K-Ras mutation in spite of large changes in ploidy and lamin B distribution

Mégnin-Chanet

Lavelle²,

Favaudon

2002

BMC Pharmacol

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Effects of the farnesyltransferase inhibitor UCF-1C/manumycin on growth and p21-ras post-translational processing in NIH3T3 cells

Cited by 12 publications

References 19 publications

Farnesyltransferase Inhibitors Induce DNA Damage via Reactive Oxygen Species in Human Cancer Cells

Farnesyltransferase Inhibitors Induce DNA Damage via Reactive Oxygen Species in Human Cancer Cells

Manumycin A inhibits triple-negative breast cancer growth through LC3-mediated cytoplasmic vacuolation death

The farnesyl transferase inhibitor RPR-130401 does not alter radiation susceptibility in human tumor cells with a K-Ras mutation in spite of large changes in ploidy and lamin B distribution

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