Proteomic identification of heat shock protein 70 as a candidate target for enhancing apoptosis induced by farnesyl transferase inhibitor

Hu, Wei; Wu, Wei; Verschraegen, Claire F.; Chen, Ling; Li, Mao; Yeung, Sai Ching Jim; Kudelka, Andrzej P.; Freedman, Ralph S.; Kavanagh, John J.

doi:10.1002/pmic.200300547

Cited by 48 publications

(24 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…25,26 All these antiapoptotic roles suggest that Hsp70 may be involved in resistance to imatinib, similarly to its participation in other forms of drug resistance. 21,27,28 In the present study, we confirm that the K562-r cells resistant to imatinib are also resistant to nilotinib, the novel tyrosine kinase inhibitor (AMN107) that was initially developed as a potent Bcr-Abl inhibitor based on the molecular structure of imatinib. We detect by Western blotting that Hsp70 is overexpressed in K562-r cells, as compared to their imatinib-sensitive counterparts.…”

Section: Introductionsupporting

confidence: 60%

Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia

et al. 2006

View full text Add to dashboard Cite

Imatinib is an effective therapy for chronic myeloid leukemia (CML), a myeloproliferative disorder characterized by the expression of the recombinant oncoprotein Bcr-Abl. In this investigation, we studied an imatinib-resistant cell line (K562-r) generated from the K562 cell line in which none of the previously described mechanisms of resistance had been detected. A threefold increase in the expression of the heatshock protein 70 (Hsp70) was detected in these cells. This increase was not associated to heat-shock transcription factor-1 (HSF-1) overexpression or activation. RNA silencing of Hsp70 decreased dramatically its expression (90%), and was accompanied by a 34% reduction in cell viability. Overexpression of Hsp70 in the imatinib-sensitive K562 line induced resistance to imatinib as detected by a large reduction in cell death in the presence of 1 lM of imatinib. Hsp70 level was also increased in blast cells of CML patients resistant to imatinib, whereas the level remained low in responding patients. Taken together, the results demonstrate that overexpression of Hsp70 can lead to both in vitro and in vivo resistance to imatinib in CML cells. Moreover, the overexpression of Hsp70 detected in imatinibresistant CML patients supports this mechanism and identifies potentially a marker and a therapeutic target of CML evolution.

show abstract

Section: Introductionsupporting

confidence: 60%

Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia

et al. 2006

View full text Add to dashboard Cite

show abstract

“…It has been previously reported that up-regulation of hsp70 can protect ovarian cancer cells from FTI-induced apoptosis (25). In addition, blockade of hsp27 expression has been shown to overcome PS-341 resistance in lymphoma cell lines (26,27).…”

Section: Microarray Analysismentioning

confidence: 99%

Characterization of a R115777-Resistant Human Multiple Myeloma Cell Line with Cross-Resistance to PS-341

Buzzeo

Enkemann

Nimmanapalli

et al. 2005

Clinical Cancer Research

View full text Add to dashboard Cite

The farnesyl transferase inhibitor R115777 has been found to have clinical activity in diverse hematopoietic tumors. Clinicalefficacy, however, doesnot correlate with Rasmutationstatus orinhibition of farnesyl transferase. To further elucidate the mechanisms by which R115777 induces apoptosis and to investigate drug resistance, we have identified and characterized a R115777-resistant human myeloma cell line. 8226/R5 cells were found to be at least 50 times more resistant to R115777 compared with the parent cell line 8226/S. K-Ras remained prenylated in both resistant and sensitive cells after R115777 treatment; however, HDJ-2 farnesylation was inhibited in both lines, implying that farnesyl transferase (the drug target) has not been mutated. Whereas many 8226 lines that acquire drug resistance have elevated expression of P-glycoprotein, we found that P-glycoprotein expression is not increased in the 8226/R5 line and intracellular accumulation of R115777 was not reduced. In fact, 8226/R5 cells were insensitive to a diverse group of antitumor agents including PS-341, and multidrug resistance didnot correlate with the expressionof heat shock proteins.Comparison of gene expression profiles between resistant and sensitive cells revealed expression changes in several genes involved in myeloma survival and drug resistance. Future experiments will attempt to identify genes that are directly linked to the resistant phenotype. Identification of molecules associated with R115777 and PS-341resistance is clinically relevant because both compounds are being tested in solid tumors and hematopoietic malignancies.

show abstract

“…Inhibition of the PI-3 kinase/Aktmediated cell survival and adhesion pathway by FTIs has been shown to play a role in the induction of apoptosis (9). Heat shock protein 70 may also be a target for induction of apoptosis by FTIs as well (10,11).…”

Section: Introductionmentioning

confidence: 99%

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

Pan

She

Xu³

et al. 2005

Cancer Research

Self Cite

View full text Add to dashboard Cite

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)

show abstract

Proteomic identification of heat shock protein 70 as a candidate target for enhancing apoptosis induced by farnesyl transferase inhibitor

Cited by 48 publications

References 24 publications

Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia

Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia

Characterization of a R115777-Resistant Human Multiple Myeloma Cell Line with Cross-Resistance to PS-341

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

Contact Info

Product

Resources

About