Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells
© Horibe et al.; licensee BioMed Central Ltd. 2012
Received: 1 March 2012
Accepted: 16 August 2012
Published: 22 August 2012
Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo.
In this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition.
These results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.
KeywordsClient proteins Heat shock protein 90 Hybrid peptide Molecular chaperone Unfolded protein response Glioblastoma
Malignant gliomas are the most commonly diagnosed malignant adult primary brain tumors, and median survival for glioblastoma (GB) is 12–15 months . Targeted therapies, as single agents, have failed to offer long-term survival benefit, despite objective initial responses . Heterogeneity and a complex molecular pathology of GB contribute to the lack of therapeutic success. It was previously reported that GB cells were dependent on a range of activated oncoproteins and signaling pathways which require heat-shock protein 90 (Hsp90) function .
Hsp90 is an abundant cytosolic molecular chaperone found within multimeric chaperone complexes known to participate in regulating protein homeostasis in cells. It is also well known that Hsp90 assists maturation of more than 200 proteins, which include transmembrane tyrosine kinase (Her2 and EGFR), metastable signaling proteins (Akt, K-ras, and Raf-1), mutated signaling proteins (p53 and v-Src), chimeric signaling proteins (Bcr-Abl), cell-cycle regulators (Cdk4 and Cdk6), and steroid receptors (androgen, estrogen, and progesterone receptors) [4–8]. Therefore, Hsp90 plays a unique role in cellular homeostasis, and consequently Hsp90 has emerged as a promising anticancer target.
On the other hand, it is also well known that cells respond to a wide variety of stresses through the transcriptional activation of genes that harbor stress elements in their promoters, and cells can also respond to stresses that are specific to individual organelles. For example, the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER) activate the ER unfolded protein response (erUPR) [9, 10]. The erUPR is a complex signaling network that enhances cell survival by limiting the accumulation of unfolded or misfolded proteins in the ER [9, 10]. The erUPR has three signaling pathways – inositol-requiring 1 (IRE1), PKR-like ER kinase (PERK), and ER-localized transmembrane protein ATF6 [9, 10] – wherein PERK plays a major role in ER stress-induced translational attenuation . ATF6 is activated by proteolysis and binds in the presence of NF-Y directly to a cis-acting element (CCAAT-N9-CCACG) to induce ER stress-inducible proteins which include molecular chaperones , whereas IRE1 mediates the unconventional splicing of XBP1 mRNA, thereby converting it to a potent erUPR transcriptional activator . These transcription factors lead to coordinated induction of diverse erUPR target genes, such as the ER-resident molecular chaperones glucose-regulated proteins 78 (GRP78; also known as Bip) and 94 (GRP94), for cell survival [14, 15]. However, the erUPR also induces the up-regulation of the chop gene, encoding a bZIP transcriptional factor CHOP (C/EBP homology protein), which is regulated by a number of transcriptional and translational mechanisms . The induction of CHOP by the erUPR can lead to the transcriptional activation of Bim, leading in turn to apoptosis in the case of intolerable levels of the erUPR in the cells . A broad range of cancer-types rely on ER protein-folding machinery to correctly fold key signaling pathway proteins, and erUPRs are strongly induced in various tumors . Recently, accumulating evidence has demonstrated that the erUPR is an important mechanism required for cancer cells to maintain malignancy and therapy resistance. Hence, the erUPR may be also a significant target by which to improve cancer chemotherapy .
We previously reported that a newly designed Antp-TPR hybrid peptide inhibits the interaction of Hsp90 with tetratricopeptide repeat 2A domain (TPR2A) of p60/Hsp-organizing protein (Hop), has selective cytotoxic activity that allows it to discriminate between cancer and normal cell lines, and induces effective antitumor activity in a xenograft model of human pancreatic cancer in mice . However, the detailed mechanism of cancer-cell-killing by Antp-TPR peptide still remains obscure. Recently it was reported that the Hsp90 antagonist geldanamycin and its derivative 17-allylamino-demethoxygeldanamycin (17-AAG) lead to ER stress-induced apoptosis in rat histiocytoma , whereas it was also reported that retaspimycin (IPI-504), which is a novel and soluble type of Hsp90 inhibitor derived from geldanamycin, blocks the UPR in multiple myeloma cells . It is important for the further elucidation of cancer treatment targeting Hsp90 to address the functional mechanism of cancer-cell killing by Antp-TPR hybrid peptide. Here we report the mechanisms that Antp-TPR hybrid peptide uses to induce cancer-cell killing through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf on GB cells. We also show that Antp-TPR hybrid peptide increases the erUPR and cytotoxic activity towards GB cells in the erUPR condition.
Cytotoxic activity of Antp-TPR hybrid peptide to GB cell lines
Inhibitory concentration (IC 50 ) of Antp-TPR peptide of glioma cells
26.53 ± 5.78
28.27 ± 7.23
35.70 ± 0.92
Cytotoxic mechanism of Antp-TPR in GB cells
Molecular diversity of the cancer-cell-killing mechanism of Antp-TPR peptide and 17-AAG
Increase of the erUPR by Antp-TPR peptide in GB cells
Increase of cytotoxic activity of Antp-TPR peptide in the erUPR
In this study we have shown that global subcellular targeting of the Hsp90 network with Antp-TPR hybrid peptide provides effective cytotoxic activity against GB cells (U251, A172, and SN19). It was found that Antp-TPR peptide mechanistically induced a simultaneous degradation of multiple Hsp90 client proteins such as p53, CDK4, Akt, and cRaf in the cytosol, triggering cancer-cell killing. GB cells are dependent on a range of activated oncoproteins and signaling pathways that require Hsp90 function . Thus, Hsp90 inhibitors have been interesting agents with which to improve treatment results in GB, a primary brain tumor with a particularly dismal prognosis . Although Hsp90-based therapy has been intensely pursued as a paradigm of network-oriented drug discovery [31–33], the clinical results by these agents have so far been inferior to expectations, producing only small gains in cancer patients . In this study we found that the molecular activity of Antp-TPR is diverse from 17-AAG in its cancer-cell-killing mechanism (Figures 2 and 3, Additional files 2 and 3). In addition, Antp-TPR peptide did not cause the up-regulation of Hsp27, Hsp70, and Hsp90 proteins after treatment with this peptide (Figures 2 and 3). It was previously reported that the conventional Hsp90 ATPase inhibitors induce a compensatory up-regulation of Hsp70 that likely correlates with the decrease of anticancer activity [24, 25]. It was also reported that 17-AAG induces the up-regulation of Hsp27, elevation of glutathione concentration, and resistance to this compound through a glutathione-mediated mechanism in cancer cells . We also found that Antp-TPR peptide did not increase the concentrations of glutathione after treatment with this peptide in cancer cells (data not shown). Taking together this evidence and the results of our study, Antp-TPR hybrid peptide might have an additional advantage over Hsp90-targeted small compounds such as geldanamycin and 17-AAG.
Recently, Saito et al.  reported that the antidiabetic biguanides metformin, buformin, and phenformin could work as erUPR modulators during glucose deprivation in cancer cells, and that disrupting the erUPR could be an attractive approach for selective cancer-cell killing. Meanwhile, depending on the type of tumor, compounds which induce and increase the erUPR can also be used as anticancer agents such as the proteasome inhibitor bortezomib or the Hsp90 inhibitors geldanamycin and 17-AAG [36, 37]. In this study, it was also found that Antp-TPR increased the erUPR through both activation of Bip promoter and up-regulation of transcriptional levels of Bip and CHOP, and then elevated the cytotoxic activity against GB cells (Figures 4 and 5). Since the Antp-TPR peptide did not increase the promoter activity of YME1L1 and GCP60 after induction of the mtUPR and Golgi stress (Additional file 4A), it is suggested that Antp-TPR might affect the erUPR specifically in cancer cells. In addition, Antp-TPR peptide did not increase cytotoxic activity against normal cells even in the erUPR condition (Figure 5). Interestingly, although 17-AAG also increased activation of the Bip promoter, the effective enhancement of the cytotoxic activity to GB cells by this compound was not observed (Figures 4 and 5). Thus, it is possible that Hsp proteins such as Hsp70 and Hsp90, up-regulated by the treatment of 17-AAG, might prevent the enhancement of cytotoxic activity against GB cells even during the erUPR.
It is well known that cancer cells are often exposed to hypoxia, nutrient starvation, oxidative stress, and other types of metabolic dysregulation that cause ER stress and activation of the erUPR. Depending on the duration and degree of ER stress, the erUPR can provide either survival signals by activating adaptive and antiapoptotic pathways or death signals by inducing a cell-death program. Sustained induction or repression of erUPR pharmacologically may thus have beneficial and therapeutic effects against cancer. In fact, glucose deprivation as well as hypoxia are common features in poorly vascularized solid tumor but are not observed in normal tissue. Interestingly, since Antp-TPR peptide increased cytotoxic activity against cancer cells after induction of the erUPR it is expected that it might exert effective antitumor activity if it penetrates a tumor. Although it is suggested that peptides are relatively easily inactivated by serum components in the human body, there are currently many candidate anticancer peptides which target intracellular molecules or organelles [38, 39]. In fact, we previously reported that a 1 mg/kg dosage of Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice . This dosage of Antp-TPR in vivo is supposed to be lower than the concentrations estimated from IC50 values tested in vitro compared with small compounds such as 17-AAG. As mentioned above, Antp-TPR may have an advantage over small compounds in terms of effective antitumor activity.
Our current data describe how Antp-TPR has the molecular features of a novel class of global Hsp90 inhibitor, which is capable of simultaneously disabling the multiple pools of client proteins to increase the erUPR in cancer cells. Such an approach might offer a new therapeutic approach for the management of heterogeneous and otherwise malignant human tumors, including GB. Taken together with our previous study , Antp-TPR hybrid peptide may provide a potent and novel type of selective anticancer therapy through its action as an erUPR modulator. Thus, the findings of this study will assist in the further elucidation of cancer treatment targeting Hsp90.
Materials and methods
Anti-Hsp90, anti-Hsp70, and anti-Hsp27 antibodies were purchased from Stressgen Bioreagents (Ann Arbor, MI, USA). Anti-c-Raf, anti-Akt, andCDK4 antibodies were purchased from Cell Signaling (Danvers, MA, USA). Anti-p-53 and anti-βactin antibodies, and 2-phenylethynesulfonamide (PES; also called pifithrin-μ) were purchased from Sigma (St Louis, MO, USA). 17-AAG was purchased from InvivoGen (San Diego, CA, USA). Thapsigargin (Tg), tunicamycin, and other reagents were mostly obtained from Nacalai Tesque (Kyoto, Japan). All reagents were of reagent grade.
Cells and cell culture
Human GB cell lines (A172 and SN19) were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA), and U251 cell line was obtained from the National Cancer Institute, Frederick Cancer Research Facility, Division of Cancer Treatment Tumor Repository Program (Frederick, MD, USA). The normal pancreatic epithelial (PE) cell line ACBRI 515 was purchased from the European Collection of Cell Culture (ECACC, Salisbury, UK). Cells were cultured in RPMI-1640 (U251, A172, and SN19 cells) or CSC (ACBRI 515 cells) containing 10% fetal bovine serum, 100 μg/ml penicillin, and 100 μg/ml streptomycin at 37°C and in an atmosphere of 5% CO2/95% air.
Peptides used in this study were synthesized by the American Peptide Company (Sunnyvale, CA, USA). Peptides were dissolved in water and buffered to pH 7.4 as described previously . The TPR sequence 301 K-312 K (KAYARIGNSYFK; TPR)  was made cell-permeable by addition of helix III of the cell-penetrating Antennapedia homeodomain sequence (underlined) , as follows: RQIKIWFQNRRMKWKK KAYARIGNSYFK (Antp-TPR).
Western blot analyses were carried out as described previously [20, 41]. Briefly, protein extracts were prepared from cells lysed with buffer containing 1% (v/v) Triton X-100, 0.1% (w/v) SDS, and 0.5% (w/v) sodium deoxycholate, separated by SDS-PAGE and transferred to nitrocellulose filters by iBlot system (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s protocol. Quenched membranes were probed with antibodies and analyzed using enhanced chemiluminescence reagent (GE Healthcare Bioscience, Uppsala, Sweden) with a LAS-3000 LuminoImage analyzer (Fujifilm, Tokyo, Japan).
The total RNA in cells was isolated using the NucleoSpin RNA kit (Macherey-Nagel, Düren, Germany). For RT reactions 0.5 μg of RNA sample was used, and the reaction was performed in a final volume of 10 μl of reaction mixture using the ReverTraAce RT kit (TOYOBO, Osaka, Japan). Each 1 μl aliquot of cDNA was amplified in a final volume of 50 μl of PCR mixture. Specific primers were as follows: cRaf, 5′-TGCAGTAAAGATCCTAAAGGTTGTC-3′ and 5′-AATTAGCTGGAACATCTGAAACTTG-3′; Akt, 5′-GACTGACACCAGGTATTTTGATGAG-3′ and 5′-ATTAAATACAGATCATGGCACGAG-3′; CDK4, 5′-GAGCTCTGCAGCACTCTTATCTACA-′ and 5′-GTCATTAAGGCAGCAAAGTAATCTCT-3′; Bip, 5′-TCTACAGCTTCTGATAATCAACCAAC-3′ and 5′-TCATTGGTGATTGTGATCTTATTTTT-3′; CHOP, 5′-ATCAAAAATCTTCACCACTCTTGAC-3′ and 5′-ACTTTCCTTTCATTCTCCTGTTCTT-3′; Hsp27, 5′-GCAGGACGAGCATGGCTACA-3′ and 5′-CTCGTTGGACTGCGTGGCTA-3′; Hsp70, 5′-GCCATGACGAAAGACAACAAT-3′ and 5′-CTTTGTACTTCTCCGCCTCCT-3′; Hsp90, 5′-ACTACACATCTGCCTCTGGTGATGA-3′ and 5′-TGTTTCCGAAGACGTTCCACAA-3′; glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 5′-GTCTTCACCACCATGGAGAAGGCT-3′ and 5′-CATGCCAGTGAGCTTCCCGTTCA-3′. GAPDH was used as an internal control.
PCR product was run on a 1% agarose gel for UV analysis.
Quantitative real-time PCR analysis
Quantitative real-time PCR analysis was carried out using the SYBR Green Real-time PCR Master Mix kit (TOYOBO) on the Mx3000p Real-time QPCR System (Stratagene, La Jolla, CA, USA). Amplification was performed under the following conditions: after an initial denaturation step of 95°C for 60 s: 45 cycles of 95°C for 15 s, 60°C for 15 s, and 72°C for 45 s. The primers were the same as for RT-PCR analysis (see previous section).
Assay for cell viability
Cell viability was determined by WST-8 assay as described previously . Briefly, cells were seeded onto 96-well plates at 2000–3000 cells/well. After incubating with the test peptides, the assay for cell viability was carried out using Living Cell Count Reagent SF (Nacalai Tesque) according to the manufacturer’s protocol. Absorbance was measured at a wavelength of 450 nm using a 96-well microplate reader (GE Healthcare Bioscience). Cytotoxic activity was calculated from the percentage of cell viability; 0% cell viability was defined as 100% cytotoxic activity (100% cell-killing activity).
A reporter assay was carried out as described previously . Briefly, GB cells (U251, A172, and SN19) were transfected with firefly luciferase-containing reporter plasmids of the Bip promoter (pBipPro-Luc), in which the Bip promoter region was cloned as described previously . The Renilla luciferase-containing plasmid pRL-SV40 (Promega, Madison, WI, USA) was used as an internal control. The relative activity of firefly luciferase to Renilla luciferase (mean ± SD from triplicate determinations) was determined using the Dual-Glo Luciferase Assay System (Promega). 0.05-0.5 μM of Tg was used for the induction of erUPR depend on the number of cells. Induction of mitochondrial UPR (mtUPR) and Golgi apparatus stress was carried out as described previously [28, 29].
Flow cytometry assay
Flow cytometry assay was performed as described previously [20, 42]. Briefly, after incubation with or without Antp-TPR peptide or Tg, cells were collected and washed twice with PBS. Following this, the cell pellets were resuspended. Flow cytometry (Becton Dickinson) analysis was performed using the Annexin V-Fluorescein Staining Kit (Wako) according to the manufacturer’s protocol. Data were analyzed using CellQuest Software.
Analysis of mitochondrial membrane potential
Change of mitochondrial membrane potential was evaluated as described previously . Briefly, cells were labeled for 30 min with 5 μg/ml mitochondrial membrane potential-sensitive fluorescent dye, JC-1 (Invitrogen, Carlsbad, CA, USA), in a glass-bottomed dish after treatment with or without Antp-TPR or Tg, and then confocal images were taken using an Olympus FV 1000 confocal laser scanning microscope (Olympus, Tokyo, Japan).
All values are expressed as the mean ± SD and statistical significance was determined using the Student t-test with statistical significance assessed with a probability value less than 0.05.
antennapedia homeodomain sequence
activation transcription factor 6
cyclin dependent kinase
epidermal growth factor
human epidermal growth factor receptor type 2
heat shock protein 90
the peptide concentration inducing 50% inhibition of cell growth
phosphate and tensin homolog deleted on chromosome 10
proto-oncogene serine/threonine-protein kinase
We thank Dr. Koji Ohara, Kumi Kodama, Nana Kawaguchi, Keiko Shimoura, and Maiko Yamada (Department of Pharmacoepidemiology, Kyoto University) for technical assistance in tissue culturing and advice on using confocal laser microscopy. This study was supported by the Grant-in-Aid for Young Scientist (A) (grant no. 23680089) and Young Scientist (B) (grant no. 24790072) from the Japan Society for the Promotion of Science (JSPS). This study was also conducted in part by a collaboration research fund from Olympus Corporation.
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