Bcl-2 overexpression contributes to laryngeal carcinoma cell survival by forming a complex with Hsp90β

  • Authors:
    • Sai Li
    • Jincheng Li
    • Tian Hu
    • Chuhong Zhang
    • Xiu Lv
    • Sha He
    • Hanxing Yan
    • Yixi Tan
    • Meiling Wen
    • Mingsheng Lei
    • Jianhong Zuo
  • View Affiliations

  • Published online on: December 7, 2016     https://doi.org/10.3892/or.2016.5295
  • Pages: 849-856
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Abstract

Laryngeal carcinoma (LC) is one of the most common malignant tumors of all head and neck squamous cell carcinomas (HNSCCs). However, the molecular mechanism and genetic basis of the development of LC have not been fully elucidated. To explore the possible mechanism, targeted proteomic analysis was performed on Bcl-2-associated proteins from LC cells. According to our results, 35 proteins associated with Bcl-2 were identified and Hsp90β was confirmed by co-immunoprecipitation and western blot analysis. Protein‑protein interaction (PPI) analysis indicated that Bcl-2‑Hsp90β interactions may be involved in the anti-apoptotic progression of LC. Further results revealed that disruption of the Bcl-2-Hsp90β interaction inhibited the anti-apoptotic ability of Bcl-2 and decreased the caspase activation in LC, which has broad implications for the better understanding of tumor formation, tumor cell survival and development of metastasis due to Bcl-2. Collectively, we report the mechanism by which Bcl-2 functions in LC as an anti-apoptotic factor in relation to its association with proteins and potentially identify a Bcl-2/Hsp90β axis as a novel target for LC therapy.

Introduction

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease composed of hypopharyngeal, oropharyngeal, oral, and laryngeal squamous cell carcinoma. Laryngeal carcinoma (LC) is one of the most common malignant tumors among HNSCCs. As an etiologically multifactorial disease, carcinogenesis of laryngeal carcinoma may result from genetic and environmental factors (1). Previous study on the origin of LC suggests that genetic alterations in tumor-suppressor genes and proto-oncogenes in multiple cellular pathways may be important in multistage LC carcinogenesis. However, the molecular mechanism and genetic basis of the development of LC have not fully been elucidated.

Overexpression of Bcl-2 in primary tumors is associated with tumor cell differentiation, tumor metastasis, recurrence, and poor prognosis in patients (2) and appears to suggest apoptosis resistance in many types of cancer (3), including HNSCC (46). Overexpression of Bcl-2 is also related to chemotherapy resistance (4). However, molecular targeting of Bcl-2 with small-molecule inhibitors or short peptides was found to promote apoptosis and chemosensitivity in HNSCC cells (7,8). These studies suggest that Bcl-2 plays a crucial role in the development and progression of cancer.

In the present study, we report the mechanism by which Bcl-2 functions in LC as an anti-apoptotic factor in relation to its association with proteins by proteomes. Our data provide novel evidence that Hsp90β is associated with Bcl-2 and that this interaction facilitates optimal Bcl-2 anti-apoptotic function. Further results showed that disruption of Bcl-2-Hsp90β interaction inhibited the anti-apoptotic ability of Bcl-2 and decreased the caspase activation in LC, which will have broad implications for the better understanding of tumor formation, tumor cell survival, development of metastasis due to Bcl-2 and potentially identify a Bcl-2/Hsp90β axis as a novel target for LC therapy.

Materials and methods

Reagents

Mouse monoclonal anti-Bcl-2, anti-GAPDH, and anti-Hsp90β antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Anti-mouse antibody was purchased from Abcam, Inc. (Cambridge, MA, USA). Mercaptoethanol, iodoacetamide, and HCl were purchased from Sigma-Aldrich (St. Louis, MO, USA). Bromophenol blue, bis, TEMED, Commassie Brilliant Blue G-250, molecular weight marker, Tris-base, SDS, glycine, secondary antibodies conjugated with horseradish peroxidase, and the enhanced chemiluminescence (ECL) system were obtained from Amersham Biosciences (Stockholm, Sweden). Sequencing-grade modified trypsin was purchased from Promega Corp. (Madison, WI, USA). PVDF membranes and ZipTip C18 columns were obtained from Millipore Corp. (Boston, MA, USA).

Cell and cell culture

The HNSCC cell line SCC10A was derived from the primary lesion of a larynx carcinoma, and has been extensively characterized for its in vitro and in vivo phenotypes (9). Cells were normally maintained at low passage in Dulbeccos modified Eagles medium (DMEM) supplemented with 10% fetal bovine serum (FBS) (both from Invitrogen), 100 U/ml penicillin and 100 µg/ml streptomycin.

Co-immunoprecipitation

LC SCC10A cells were lysed at 4°C for 30 min in a lysis buffer [50 mmol/l Tris (pH 7.5), 500 mmol/l NaCl, 1% Triton X-100, 0.5% sodium deoxycholate, 0.1% SDS, 10 mmol/l MgCl2, and complete protease inhibitor mixture (Roche Molecular Biochemicals, Mannheim, Germany)]. The lysates were centrifuged at 11,000 rpm for 15 min at 4°C. Protein concentrations were measured with the bicinchoninic acid protein assay kit (Pierce, Rockford, IL, USA). The clarified supernatants were collected and used immediately for co-immunoprecipitation. Approximately 500 mg of total protein was first precleared with control (non-immune) serum, bound to 100 µl protein G-Sepharose (Amersham Biosciences). The clarified supernatants were then incubated with the anti-Bcl-2 antibody (10 µg) for 6 h. Protein G-Sepharose (100 µl) was added and the mixture was incubated overnight at 4°C. Samples were centrifuged for 30 sec and washed three times with lysis buffer, and run on a SDS-PAGE. Subsequently, SDS-PAGE electrophoresis was performed and proteins in the gels were detected by Coomassie blue R-250 staining, followed by in-gel trypsin digestion and MS analysis as previously described by us (10). For western blot analysis, proteins in the gels were transferred to nitrocellulose membranes (Millipore Corp.). Then the membranes were incubated with an anti-Bcl-2 or an anti-Hsp90β antibody. The Bcl-2 antibody was then replaced by the non-immune IgY antibody (GenWay Biotech, Inc., San Diego, CA, USA) which was used as a negative control.

MS and database analysis

ESI-Q-TOF-MS analysis of proteins was performed as described by Cheng et al and Huang et al, respectively (10,11).

Western blot analysis

The immunoprecipitated complexes or cell lysates were separated by 10% SDS-PAGE, and transferred to nitrocellulose membranes (Millipore Corp.). Blots were blocked with 5% non-fat dry milk for 30 min at room temperature and washed three times with phosphate-buffered saline (PBS) buffer. Then they were incubated with primary anti-Bcl-2, anti-Hsp90β, or anti-GAPDH antibodies overnight at 4°C, followed by incubation with a horseradish peroxidase-conjugated secondary antibody for 1 h at room temperature. The signal was visualized with ECL detection reagent. GAPDH was detected simultaneously using mouse anti-GAPDH antibody as a loading control.

Bioinformatic analysis

Molecule function classification and cluster analysis were performed through the GO and Cluster program DAVID (http://david.abcc.ncifcrf.gov/). The default parameters of classification in terms of stringency in the DAVID Cluster program were medium. Protein-protein interaction (PPI) analysis was performed using VisANT software (version 3.15) (http://visant.bu.edu/) (12).

RNA interference analysis

For RNA interference analysis, the cells were transfected with Hsp90β siRNA or control siRNA (Dharmacon, Inc.) using the Lipofectamine 2000 reagent (Invitrogen) according to the siRNA transfection protocol provided by the manufacturer. Briefly, the day before transfection, SCC10A were plated into 6-well plates at the density of 105 cells/ml in DMEM containing 10% FBS. When the cells reached 60–80% confluence, they were transfected with 10 nmol/l of Hsp90β siRNA or control siRNA after a preincubation for 20 min with siRNA transfection reagent in siRNA transfection medium. Four hours after the beginning of the transfection, the medium was replaced with DMEM containing 10% FBS and the cells continued to culture for an additional 44 h. At the end of the transfection, the Hsp90β expression level in the cells was determined by western blot analysis.

Caspase activity assay

The caspase-3/7 fluorometric assay kit (Promega Corp.) was used to measure caspase-3/7 activity following the manufacturers instructions.

Immunohistochemistry

Immunohistochemical analysis of Bcl-2 and Hsp90β was carried out with formalin-fixed and paraffin-embedded tissue sections using the standard immunohistochemical technique according to a report by Zuo et al (13).

Statistical analysis

A Student's t-test was used for the statistical analysis, with P<0.05 considered as a significant difference.

Results

Bcl-2-associated proteins are identified by co-immunoprecipitation and MS

To isolate proteins that interact with Bcl-2, we performed a proteomic analysis of the Bcl-2 complexes using targeted proteomics (co-immunoprecipitation coupled with MS). The complex was eluted, separated on an SDS-PAGE (Fig. 1A), and subjected to in-gel trypsin digestion. The tryptic digests were analyzed through ESI-Q-TOF-MS. To control for non-specific immune complexes, the Bcl-2 antibody was replaced by a non-immune IgY antibody which was used as a negative control. Thirty-five proteins were identified in the Bcl-2 complex after removing the proteins that were not found in the replicate experiments, and subtracting the common proteins that were found in the negative control (Table I).

Table I.

Bcl-2 interacting proteins.

Table I.

Bcl-2 interacting proteins.

Protein accession nos.Protein molecular weight (Da)No. of unique peptidesScorePercentage sequence coverage (%)
4F2_HUMAN67,978.4021014.13
ACTN1_HUMAN, ACTN4_HUMAN103,043.0021202.69
ALBU_HUMAN69,348.902 2.46
COF1_HUMAN18,485.1026215.10
DDX1_HUMAN82,415.1021273.51
DDX3X_HUMAN73,227.702833.93
DDX5_HUMAN69,131.7031376.51
EIF3L_HUMAN66,711.302 5.14
GRP78_HUMAN72,316.7031156.57
GTF2I_HUMAN112,399.902412.71
GTF2I_HUMAN112,399.9031494.01
HS90β_HUMAN83,249.3042407.32
HSP7C_HUMAN70,881.80522911.50
K2C1_HUMAN66,022.3031336.37
K2C5_HUMAN62,361.601462.37
K2C5_HUMAN62,361.6031266.44
MYH9_HUMAN226,519.502851.12
PI51A_HUMAN62,617.4031376.94
PKP3_HUMAN87,066.702653.76
PLEC1_HUMAN531,765.9083611.79
PSPC1_HUMAN58,726.50523611.10
RL11_HUMAN20,235.201557.87
RL22_HUMAN14,769.301468.59
RS16_HUMAN16,427.9026715.10
RS23_HUMAN15,789.701907.69
SFPQ_HUMAN76,131.502752.97
TBB5_HUMAN49,652.60413411.70

All 35 protein bands were excised from the stained gels, in situ digested with trypsin and analyzed by MALDI-TOF MS. A total of 35 differential protein bands were identified. The MALDI-TOF mass spectrometry map and database query result of the representative bands of Hsp90β are presented in Fig. 1B and C. The total of the monoisotopic peaks was input into the Mascot search engine to search the Swiss-Prot database, and the query result showed that the protein bands belonged to Hsp90β (Fig. 1C and D). The annotation of all the identified proteins is summarized in Table I.

Validation of the interactome of Bcl-2

To confirm the MS analysis results, we selected the protein of interest, Hsp90β, and detected its binding to Bcl-2 by co-immunoprecipitation and western blot analysis based on the availability and quality of the available antibodies. As shown in Fig. 2A, Hsp90β was detected in the Bcl-2 immune complex but not in the control. Concurrently, Bcl-2 was detected in the Hsp90β immune complex but not in the control (Fig. 2B). These data showed that the MS analysis results are reliable for bioinformatics and PPI analysis.

PPI analysis

In order to understand the interaction among the Bcl-2-associated proteins, PPI analysis was performed using VisANT software (http://visant.bu.edu/), a data integrating visual framework for biological networks and modules. Entrez-gene IDs of 35 Bcl-2-associated proteins were input into the VisANT software and a complex net was obtained. The PPIs are presented in Fig. 3A and it was revealed that Bcl-2 could interact with Hsp90β. In order to detect the relationship between Hsp90β and susceptibility to apoptosis in LC cells, we chose the Bcl-2/Hsp90β interaction for further study.

Hsp90β expression is necessary for Bcl-2 anti-apoptosis

In order to detect whether Hsp90β is important to the anti-apoptotic function of Bcl-2, we applied geldanamycin (GA), as a specific inhibitor of Hsp90β, to study the chaperone function of Hsp90β in its association with Bcl-2. LC cells were treated with various concentrations of GA for 24 h. As expected, the data showed that the association of Hsp90β with Bcl-2 was effectively blocked in a dose-dependent manner by GA in the Bcl-2 immunoprecipitation (Fig. 3B). Moreover, caspase-3/7 activities in the cells treated with GA showed a dose-dependent increase (Fig. 3C), which suggested that the inhibition of the chaperone function of Hsp90β in its association with Bcl-2 decreased the ability of the anti-apoptotic efffect of Bcl-2.

Knockdown of Hsp90β decreases the ability of anti-apoptosis by Bcl-2

To further study the function of the Hsp90β-Bcl-2 association, specific siRNA of Hsp90β was carried out to knock down the expression of Hsp90β. The results revealed that the protein level of Hsp90β was significantly decreased 48 h after the treatment with the specific Hsp90β RNAi. However, the change in expression of Hsp90β was not detected in the untreated cells or the cells treated with scrambled siRNA as determined by western blot analysis (Fig. 4A). Concurrently, it is of note that the knockdown of Hsp90β expression led to a significant increase in the activity of caspase-3/7 in the SCC10A cells compared to the control cells (Fig. 4B).

Correlation between Bcl-2 and Hsp90β expression and clinicopathological factors in LC

In order to further verify whether the Bcl-2 target we identified is also associated with Hsp90β in vivo, we examined the expression levels of the Bcl-2 and Hsp90β proteins, which are both actually highly expressed in LC (Fig. 4C). By Spearman correlation analysis it was concluded that there was a positive correlation between the expression of Bcl-2 and Hsp90β in laryngeal squamous cell carcinoma (P<0.05) (Table II). The expression of Bcl-2 and Hsp90β in LC tissues was not associated with the age and gender of the patients (P>0.05) whereas it was correlated with tumor differentiation, clinical stage and lymph node metastasis (P<0.05) (Table III).

Table II.

Correlation between Bcl-2 and Hsp90β expression in LC.

Table II.

Correlation between Bcl-2 and Hsp90β expression in LC.

Hsp90β

+
Bcl-2
+38  2
  611

[i] LC, laryngeal carcinoma.

Table III.

Correlation between Bcl-2 and Hsp90β expression and clinicopathologic factors in LC.

Table III.

Correlation between Bcl-2 and Hsp90β expression and clinicopathologic factors in LC.

Bcl-2 Hsp90β


Parameter+P-value+P-value
Overall1740 1344
Age (years) 0.340 0.381
  >60  722   821
  ≤601018   523
Gender 0.279 0.240
  Male1136   839
  Female  6  4   5  5
Tumor differentiation 0.023 0.006
  Well/moderate1420 1222
  Poor  320   122
Lymph node metastasis 0.014 0.010
  Yes  526   328
  No1214 1016
TNM stage 0.025 0.002
  I–II  729 1323
  III–IV1011   021

[i] LC, laryngeal carcinoma.

Discussion

Human Bcl-2 is located near the junction of chromosomes 18 and 14 (t14;18) and has been discovered in the tumor cells of follicular lymphoma patients. The chromosome translocation results in misregulation of the normal Bcl-2 expression pattern, which leads to abnormal cell growth and certainly contributes to the development of certain types of tumors (14,15). Bcl-2 overexpression occurs in a wide range of human cancers (16) and causes resistance to apoptosis, autophagic-associated cell death and treatment (1619). Elevated expression of Bcl-2 in some tumors is often associated with enhanced invasion and metastasis (2022), shorter survival time and generally poorer clinical outcomes (23). Thus, Bcl-2 plays an important role in the orientation and development of tumors. Bcl-2 is one of the key regulators of apoptosis because it endows a survival advantage on cells by protecting cells from apoptotic death (17). However, this unknown mechanism needs to be elucidated, especially in LC. In the present study, we investigated in detail, the molecular pathways by which Bcl-2 overexpression contributes to LC cell survival by forming a complex with Hsp90β (Fig. 5).

VisANT extends the application of the GO database, in network visualization, analysis and inference as an integrative software platform used for the visualization, mining, analysis and modeling of biological networks (12,24). VisANT supports biological network mining and analysis, meaning that it is able to find previously unidentified networks, annotate them, and display their hierarchical organization (25). VisANT allows the different types of networks to analyze the correlations between disease, therapy, genes and drugs systematically (26). VisANTs ability to use nodes to model more complex entities such as protein complexes or pathways allows for more informative visualizations. VisANT also implements algorithms for analyzing node degrees, clusters, path lengths, network motifs and network randomizations (27). In this study, PPI was performed using VisANT software to discover how Bcl-2 interacts with its associated proteins. The results indicated that Bcl-2 interacts with Hsp90β, which regulates cell apoptosis.

Heat shock proteins represent a diverse group of chaperones that play a critical role in the protection of cells against numerous environmental stresses (27). Heat shock proteins also carry out the functions of the folding of synthesized proteins, and play a role in the maturation and activity of many proteins. Many Hsp90 clients such as Raf, Bcr-Abl, and C-kit are oncoproteins that are either mutated or overexpressed in cancer cells, which in turn lead to the disregulation of cell growth and proliferation (28). Hsp90 can regulate cell motility, inflammation, angiogenesis, matrix remodeling, tumor progression and metastasis (27). Hsp90β is one of the isoforms of Hsp90, which plays an important role in forming a multiprotein complex with ATPase activity. It is also involved in the folding, activation and assembly of several proteins, such as the tumor-suppressor protein p53, the NOS family members, Akt/protein kinase B and Raf-1 (29,30), which result in signal transduction and transcriptional regulation. Hsp90β is a calcium-binding protein and a novel regulatory factor of MMP-13 expression in osteoarthritic chondrocytes (31). As many client proteins of Hsp90 control cell survival, proliferation, and apoptosis, Hsp90 is closely associated with human health, especially tumors. Concurrently, the expression of Hsp90 is 2- to 10-fold higher in tumor cells than in normal cells (32). Therefore, Hsp90 has emerged as an important target in cancers such as non-small cell lung cancer, melanoma and breast cancer (33) in recent years.

In the present study, GA, a benzoquinone ansamycin antibiotic, has been used as an inhibitor of Hsp90β since it specifically binds to the ATP/ADP pocket binding site in the N-domain of Hsp90β, which leads to disruption of the Hsp90β interaction with certain proteins. Thus, the GA inhibitor was applied to test the chaperone function of Hsp90 in its association with Bcl-2. Co-immunoprecipitation experiments showed that Hsp90β binding to Bcl-2 was abrogated by GA, which suggests that Hsp90β may fail to bind to Bcl-2. We also found that decreased Hsp90β binding to Bcl-2 by GA led to these cells being less resistant to apoptosis than the control cells. As predicted, GA induced cell apoptosis to a greater degree when compared with the control. Notably, the data suggest that GA has a potent antitumor effect and may result in its use in clinical trials in LC in the future.

In this study, we immunohistochemically determined Bcl-2 and Hsp90β expression in 57 patients with LC, and found a 70.18 and 77.20% positive frequency, respectively, similar to that reported previously. Moreover, we showed that Bcl-2 and Hsp90β were highly expressed in tumors, and positively associated with tumor differentiation, clinical stage and lymph node metastasis. Finally we demonstrated a positive correlation between Bcl-2 expression and Hsp90β expression, when the percentage of positively stained cells was determined in the LC tissues. All in all, these aforementioned findings strongly support the relationship of Bcl-2 and Hsp90β and their role in LC.

Collectively, in the present study we found a novel molecular mechanism of anti-apoptosis via Bcl-2/Hsp90β interaction in LC, which is strong evidence for new targets for LC therapy.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (no. 81272960), the Key Research Program from the Science and Technology Department of Hunan Province, China (no. 2013WK2010, 2014SK2015) and the Key Research Program from the Ministry of Human Resources and Social Security of the People's Republic of China (2016) (no. 176).

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Spandidos Publications style
Li S, Li J, Hu T, Zhang C, Lv X, He S, Yan H, Tan Y, Wen M, Lei M, Lei M, et al: Bcl-2 overexpression contributes to laryngeal carcinoma cell survival by forming a complex with Hsp90β. Oncol Rep 37: 849-856, 2017
APA
Li, S., Li, J., Hu, T., Zhang, C., Lv, X., He, S. ... Zuo, J. (2017). Bcl-2 overexpression contributes to laryngeal carcinoma cell survival by forming a complex with Hsp90β. Oncology Reports, 37, 849-856. https://doi.org/10.3892/or.2016.5295
MLA
Li, S., Li, J., Hu, T., Zhang, C., Lv, X., He, S., Yan, H., Tan, Y., Wen, M., Lei, M., Zuo, J."Bcl-2 overexpression contributes to laryngeal carcinoma cell survival by forming a complex with Hsp90β". Oncology Reports 37.2 (2017): 849-856.
Chicago
Li, S., Li, J., Hu, T., Zhang, C., Lv, X., He, S., Yan, H., Tan, Y., Wen, M., Lei, M., Zuo, J."Bcl-2 overexpression contributes to laryngeal carcinoma cell survival by forming a complex with Hsp90β". Oncology Reports 37, no. 2 (2017): 849-856. https://doi.org/10.3892/or.2016.5295