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Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation.

ABSTRACT: The mechanism of cytotoxicity of farnesyltransferase inhibitors is incompletely understood and seems to vary depending on the cell type. To identify potential determinants of sensitivity or resistance for study in the accompanying clinical trial (Witzig et al, page 4882), we examined the mechanism of cytotoxicity of tipifarnib in human lymphoid cell lines. Based on initial experiments showing that Jurkat variants lacking Fas-associated death domain or procaspase-8 undergo tipifarnib-induced apoptosis, whereas cells lacking caspase-9 or overexpressing Bcl-2 do not, we examined changes in Bcl-2 family members. Tipifarnib caused dose-dependent up-regulation of Bim in lymphoid cell lines (Jurkat, Molt3, H9, DoHH2, and RL) that undergo tipifarnib-induced apoptosis but not in lines (SKW6.4 and Hs445) that resist tipifarnib-induced apoptosis. Further analysis demonstrated that increased Bim levels reflect inhibition of signaling from c-Raf to MEK1/2 and ERK1/2. Additional experiments showed that down-regulation of the Ras guanine nucleotide exchange factor RasGRP1 diminished tipifarnib sensitivity, suggesting that H-Ras or N-Ras is a critical farnesylation target upstream of c-Raf in lymphoid cells. These results not only trace a pathway through c-Raf to Bim that contributes to tipifarnib cytotoxicity in human lymphoid cells but also identify potential determinants of sensitivity to this agent.

SUBMITTER: Ding H

PROVIDER: S-EPMC3208295 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation.

Ding Husheng H Hackbarth Jennifer J Schneider Paula A PA Peterson Kevin L KL Meng X Wei XW Dai Haiming H Witzig Thomas E TE Kaufmann Scott H SH

Blood 20110614 18

The mechanism of cytotoxicity of farnesyltransferase inhibitors is incompletely understood and seems to vary depending on the cell type. To identify potential determinants of sensitivity or resistance for study in the accompanying clinical trial (Witzig et al, page 4882), we examined the mechanism of cytotoxicity of tipifarnib in human lymphoid cell lines. Based on initial experiments showing that Jurkat variants lacking Fas-associated death domain or procaspase-8 undergo tipifarnib-induced apop ...[more]

PMID: 21673341

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Project description:Papillary thyroid carcinoma (PTC) is one of the fastest growing endocrine system malignant carcinomas detected over the past decade. Unfortunately, more than 25% of PTC patients are characterized by their aggressiveness and subsequent metastasis; these characteristics usually indicate poor prognosis. Recently, increasing evidence has suggested that solute carrier (SLC) transporters may play a pivotal role in the initiation, invasion and metastasis of human carcinoma. However, the expression and clinicopathological significance of SLC transporters in patients with PTC remains undetermined. In this study, we aimed to elucidate how the differential expression of SLC transporters affects clinicopathological features, as well as determine the possible regulatory signaling pathways involved. Three differentially expressed SLC transporters were screened from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database using a bioinformatics approach. The results indicated that high SLC34A2 and low SLC4A4 protein expression exhibited a higher percentage of capsular invasion and extra-thyroid metastasis in patients. Logistic regression analysis showed that high SLC34A2 expression in tumors was identified as an independent risk factor for capsular invasion [odds ratio (OR)=11.400, 95% confidence interval (CI)=1.733-74.995, P=0.011] and extra-thyroid metastasis (OR=4.920, 95%CI=1.234-19.623, P=0.024), while low SLC4A4 expression in tumors was only identified as independent risk factors for extra-thyroid metastasis (OR=8.568, 95%CI =1.186-61.906, P=0.033). Specifically, for tumors with capsular invasion and extra-thyroid metastasis, the protein expression staining of SLC34A2 was markedly enhanced in the cytoplasm of follicular epithelial cells, contrastingly, SLC4A4 expression was notably weakened in the cytomembrane and nucleus. Intriguingly, both high SLC34A2 and low SLC4A4 protein expression were significantly linked to a high urinary iodine concentration in patients with PTC. Mechanistically, compared with adjacent normal thyroids, p-ERK was significantly up-regulated by 17.8% in the invading tumor; p-ERK, p-JNK, and p-P38 were markedly up-regulated by 29.2%, 67.1%, and 38.9% for metastatic tumors, respectively. Importantly, SLC4A4 negatively correlated with p-JNK (r=-0.696, P= 0.004) and p-P38 (r=-0.534, P=0.049). In conclusion, we suggest that up-regulated SLC34A2 (mainly in the cytoplasm) and down-regulated SLC4A4 (mainly in the cytomembrane and nucleus), which might be attributed to excess iodine intake, were closely linked to extra-thyroid metastasis in PTCs. Furthermore, this effect of SLC4A4 may be through the activation of JNK/P38 MAPK signaling pathway. Future in vivo and in vitro gain- or loss-of-function experiments are needed to verify these findings and further elucidate the deeper molecular mechanisms.

Dataset Information

Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation.

Publications

Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation.

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