The Geranylgeranyltransferase-I Inhibitor GGTI-298 Arrests Human Tumor Cells in G0/G1 and Induces p21WAF1/CIP1/SDI1 in a p53-independent Manner

Vogt, Andreas; Sun, Jiazhi; Qian, Yimin; Hamilton, Andrew D.; Sebti, Saı̈d M.

doi:10.1074/jbc.272.43.27224

Cited by 168 publications

(122 citation statements)

References 38 publications

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“…Furthermore, these Rho proteins were shown to promote G1-S traverse and their inhibition resulted in induction of p21waf and a G1 block (Zohn et al, 1998). RhoB was also shown to stimulate p21 WAF1/CIP1 expression, and the increase in p21waf and G1 block by GGTIs (Vogt et al, 1997) could be mediated by RhoB (Mazieres et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

Adnane

Joshi

et al. 2006

Oncogene

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Recently, we have shown that RhoB suppresses EGFR-, ErbB2-, Ras-and Akt-mediated malignant transformation and metastasis. In this paper, we demonstrate that the novel antitumor agents farnesyltransferase inhibitors (FTIs) and geranylgeranyltransferase I inhibitors (GGTIs) upregulate RhoB expression in a wide spectrum of human cancer cells including those from pancreatic, breast, lung, colon, bladder and brain cancers. RhoB induction by FTI-277 and GGTI-298 occurs at the transcriptional level and is blocked by actinomycin D. Reverse transcription-PCR experiments documented that the increase in RhoB protein levels is due to an increase in RhoB transcription. Furthermore, treatment with FTIs and GGTIs of cancer cells results in HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter. Thus, promoter acetylation is a novel mechanism by which RhoB expression levels are regulated following treatment with the anticancer agents FTIs and GGTIs.

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Section: Discussionmentioning

confidence: 99%

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

Adnane

Joshi

et al. 2006

Oncogene

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“…In addition to their e ects on ®broblasts (Rat-l and NIH3T3 cells) Vogt et al, 1996) and human tumor cells of epithelial origin (Miquel et al, 1997), GGTase I inhibitors also enhance the ability of IL±1b to induce nitric oxide synthase-2 in smooth muscle cells (Finder et al, 1997). Furthermore, GGTI-298 treatment of cells results in an induction of the cyclindependent kinase inhibitor p21 WAF but not p27 Kip (Vogt et al, 1997). Although in cultured cells GGTase I inhibitors can induce a G0/Gl-phase arrest and apoptosis it is not known whether they can suppress murine and human tumor growth in whole animals.…”

Section: Discussionmentioning

confidence: 99%

Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts

et al. 1998

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The ability of Ras oncoproteins to cause malignant transformation requires their post-translational modi®ca-tions by prenyl groups. Because K-Ras can be both farnesylated and geranylgeranylated it is not known whether both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for suppressing human tumor growth in whole animals. In this paper we report that oncogenic Ras processing, MAP kinase activation and growth in nude mice are inhibited by the farnesyltransferase inhibitor FTI-276 in H-and N-Ras transformed NIH3T3 cells; whereas in K B -Ras transformed NIH3T3 cells both FTI-276 and the geranylgeranyltransferase I inhibitor GGTI-297 are required for inhibition. Furthermore, human lung A-549 and Calu-1 carcinoma cell lines were found to co-express H-, N-and K-Ras. In Calu-1 cells, the processing of H-and N-Ras is inhibited greatly by FTI-276 but only partially by GGTI-297 whereas K-Ras processing inhibition requires both FTI-276 and GGTI-297. In contrast, in A-549 cells the processing of H-and N-Ras is inhibited only by FTI-276 and K-Ras processing is resistant to co-treatment with FTI-276 and GGTI-297. Yet, the growth in nude mice of A-549 and Calu-1 xenografts, both of which express K-Ras mutations, is inhibited by FTI-276 (80% inhibition) and GGTI-297 (60%). Furthermore, FTI-276 inhibits tumor growth of NIH3T3 cells transformed by a form of oncogenic H-Ras that is exclusively geranylgeranylated and whose processing is resistant to this inhibitor. Taken together, the results demonstrate that both FTase and GGTase I inhibitors are required for inhibition of K-Ras processing but that each alone is su cient to suppress human tumor growth in nude mice.

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“…43 In line with this, the geranylgeranyltransferase-I inhibitor GGTI-298, which prevents prenylation of this family of GTPases, arrests human tumor cells in G 0 /G 1 . 44,45 Evidence is emerging that members of the Rab superfamily of proteins may play important roles in cancer progression. 46 For example, increased Rab25 protein levels have been observed in prostate cancer, 47 transitional cell carcinoma of the bladder, 48 ovarian 49 and breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S‐phase arrest, in human myeloma cells

Roelofs¹,

Hulley²,

Meijer³

et al. 2006

Intl Journal of Cancer

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Bisphosphonates (BPs) are widely used in the treatment of osteolytic bone disease associated with multiple myeloma, and have been demonstrated to exert antitumor effects both in vitro and in vivo. However, the precise molecular mechanisms involved in the direct antitumor effects of BPs in vitro are not known. Nitrogen‐containing BPs, such as risedronate (RIS), act by inhibiting protein prenylation. A phosphonocarboxylate analogue of RIS, 3‐PEHPC, has previously been shown in osteoclasts and macrophages to specifically inhibit prenylation of Rab GTPases. The aim of this study was to identify the molecular targets of RIS and 3‐PEHPC in human myeloma cells and to determine the cellular effects of selective inhibition of Rab prenylation by 3‐PEHPC as compared to nonspecific inhibition of protein prenylation by RIS in human myeloma cells. RIS dose‐dependently inhibited prenylation of both Rap1A and Rab6, whereas 3‐PEHPC only inhibited Rab6 prenylation. Both RIS and 3‐PEHPC dose‐dependently increased apoptosis in human myeloma cells. RIS induced an accumulation of cells in the S‐phase of the cell cycle, associated with inhibition of DNA replication. In contrast, 3‐PEHPC did not cause cell‐cycle arrest. Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell‐cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3‐PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3‐PEHPC. In conclusion, our studies demonstrate that selective inhibition of Rab prenylation induces apoptosis, but not S‐phase arrest, thus identifying distinct molecular pathways that mediate the antimyeloma effect of nitrogen‐containing BPs. © 2006 Wiley‐Liss, Inc.

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The Geranylgeranyltransferase-I Inhibitor GGTI-298 Arrests Human Tumor Cells in G0/G1 and Induces p21WAF1/CIP1/SDI1 in a p53-independent Manner

Abstract: Recently we have shown that in fibroblasts (NIH 3T3and

Cited by 168 publications

References 38 publications

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S‐phase arrest, in human myeloma cells

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