Elsevier

Toxicology and Applied Pharmacology

Volume 330, 1 September 2017, Pages 53-64
Toxicology and Applied Pharmacology

Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and β catenin through activation of GSK3β

https://doi.org/10.1016/j.taap.2017.07.008Get rights and content

Highlights

  • Nano-formulated quinacrine (NQC) activates GSK3β in oral cancer stem cells (OCSCs) in vitro and ex vivo.

  • NQC induces apoptosis in OCSCs by inhibiting WNT-β catenin and HH-GLI cascade in vitro and ex vivo.

  • NQC disrupts the interaction and co-localization between GLI1 and β catenin.

  • NQC-mediated disruption of the crosstalk between GLI1 and β catenin is GSK3β dependent.

Abstract

Presences of cancer stem cells (CSCs) in a bulk of cancer cells are responsible for tumor relapse, metastasis and drug resistance in oral cancer. Due to high drug efflux, DNA repair and self-renewable capacity of CSCs, the conventional chemotherapeutic agents are unable to kill the CSCs. CSCs utilizes Hedgehog (HH-GLI), WNT-β catenin signalling for its growth and development. GSK3β negatively regulates both the pathways in CSCs. Here, we have shown that a nano-formulated bioactive small molecule inhibitor Quinacrine (NQC) caused apoptosis in oral cancer stem cells (OCSCs; isolated from different oral cancer cells and oral cancer patient derived primary cells) by down regulating WNT-β catenin and HH-GLI components through activation of GSK3β. NQC activates GSK3β in transcriptional and translational level and reduces β catenin and GLI1 as well as downstream target gene of both the pathways Cyclin D1, C-Myc. The transcription factor activity of both the pathways was also reduced by NQC treatment. GSK3β, β catenin and GLI1 interacts with each other and NQC disrupts the co-localization and interaction between β catenin and GLI1 in OCSCs in a dose dependent manner through activation of GSK3β. Thus, data suggest NQC caused OCSCs death by disrupting the crosstalk between β catenin and GLI1 by activation of GSK3β.

Graphical abstract

Schematic representation of inhibition of HH-GLI and WNT-β catenin cross talk by NQC through GSK3β. Diagram showing HH-GLI and WNT-β catenin pathway, where GLI1 and β catenin and other components were co-localized in a complex and co-ordinately regulate the downstream target genes. NQC activates GSK3β, which further phosphorylates and activates the β catenin and GLI1. Activated β catenin and GLI1 were degraded by proteosomal degradation pathway and unable to translocate into nucleus as a result growth of cells inhibited.

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Introduction

Oral squamous cell carcinoma (OSCC), a subtype of head and neck squamous cell carcinoma (HNSCC) is a global burden not only because of its significant mortality, but also for the resistance, relapses and post treatment failure (Naik et al., 2016). In spite of advanced treatment procedures (e.g. surgery, radiation and chemotherapy), the overall survival of patient remains unchanged over the last decade (Funk et al., 2002). Several lines of evidences suggest that the presence of cancer stem cells (CSCs) within the cancer cell niche are the major factor responsible for drug resistance and relapse (Vinogradov and Wei, 2012, Da Silva et al., 2012, Leon et al., 2016). Due to efficient DNA repair, high drug efflux and self-renewal potentiality, the conventional chemotherapeutic agents are unable to kill the CSCs which suggest more research is needed for the eradication of deadly disease.

The role of WNT-β catenin and Hedghog-GLI (HH-GLI) (sometimes NOTCH also) cascade for proliferation, maintenance and growth of the CSCs is well documented (Wang et al., 2012, Wang et al., 2016, Takebe et al., 2015, Koury et al., 2017). Mammalian HH-GLI signalling begins with binding of secreted HH ligands (SHH, IHH, DHH) to a transmembrane receptor PTCH. Ligand binding releases smoothened inhibition by PTCH which in turn activate and translocate GLI group of transcription factor to the nucleus for the transcription of HH target genes, Cyclin D1 and C-Myc. In the absence of HH ligand GLI family of transcription factors are ubiquitinated by a destruction complex formed of GSK3β, Casein Kinase 1 (CK1) and Protein Kinase A (PKA) (Hanna and Shevde, 2016).

In canonical WNT-β catenin signalling, in the absence of WNT stimulation, the Axin complex, consisting of GSK3β, CK1α and the tumor suppressor proteins Axin and APC, collectively phosphorylate β catenin and degrade it. When WNT protein binds to its Frizzled receptor and LRP5/6 co receptor, it stimulates LRP5/6 phosphorylation in part through the recruitment of the cytoplasmic protein Dishevelled (Zeng et al., 2005, Peng et al., 2017). Phosphorylated LRP5/6 then recruits Axin to the cell membrane, disrupts the Axin complex and thus stabilizes β catenin (Zeng et al., 2008). Accumulated β catenin subsequently enters the nucleus, binds to TCF/LEF and recruits transcriptional co activators such as Bcl9, Pygopus and CBP/p300 in order to activate its downstream target genes, such as cyclin D1, C-Myc and Survivin (Clevers, 2006, Rieger et al., 2016).Elevated HH-GLI signalling components (e.g. SMO, SHH, GLI1) promotes invasion and metastasis in OSCC through E cadherin and MMP 9 (Cavicchioli Buim et al., 2011, Fan et al., 2014). Overexpression of WNT-β catenin signalling components are also reported in HNSCC including salivary gland SCC (Wend et al., 2013). The nuclear translocation of β catenin leads to oral epithelial dysplasia by downregulating E-cadherin (Alvarado et al., 2011). It was also noted that elevated β catenin expression leads to oral carcinogenesis by inducing cyclin D1 and Ki-67 (Odajima et al., 2005).

Accumulating evidence suggests that components of WNT-β catenin and HH-GLI pathway interact in various cell types eliciting either opposing or synergistic effects (Maeda et al., 2006, Arimura et al., 2009, Song et al., 2015, Morris and Huang, 2016, Zinke et al., 2015). Veranat et al. reported the loss of WNT-β catenin signalling leads to gain of function of HH-GLI signalling in colon cancer (Varnat et al., 2009). Zinke et al. reported in medulloblastoma that physical interaction between β catenin with GLI1 leads to degradation of GLI1 thereby suppressing HH-GLI signalling (Zinke et al., 2015). On the other hand β catenin and GLI1 interaction induces malignant phenotype in glioblastoma multiforme (Rossi et al., 2011). Ectopic over expression of GLI1 in endometrial cancer leads to nuclear accumulation of β catenin leading to endometrial carcinogenesis (Liao et al., 2009). β catenin also regulates GLI1 by inducing the expression of an RNA binding protein CRD-BP that in turn binds to coding region of GLI1 mRNA and stabilizes it (Noubissi et al., 2009). Reports also suggest that GLI1 interacts with β catenin by inducing the expression of snail [Stemmer et al., 2008].

HH-GLI and WNT-β catenin inhibitors have emerged as an effective and promising molecular target for cancer treatment. Various small molecule inhibitors of HH-GLI (e.g. GANT 58, GANT61, SANT1-3, GDC0449) and WNT-β catenin (e.g. PKF115-584, CGP049090,PNU-74654, XAV 939) signalling targets the key molecular component of HH-GLI and WNT-β catenin pathways (Mas et al., 2010, Gandhirajan et al., 2010, Leal et al., 2015). They inhibits particular pathway, reduces target protein expression and ultimately inhibits cancer cell growth. But no successful outcome has appeared in clinic because these anticancer agents act on single pathway (either HH-GLI or WNT-β catenin); required high concentrations for desire action, side effect, poor PK/PD and kills only bulk of cancer cells leaving aside the CSCs. Thus to develop new drug molecule against CSCs it is utmost necessary to develop not only bio available, water soluble non-toxic bioactive compound but also understand the mechanism of crosstalk between HH-GLI and WNT-β catenin signalling.

Quinacrine (QC), an age old anti-malarial agent recently rediscovered as an anti-cancer agent. It displays anti-cancer action by variety of mechanism including activating p53, DNA damage, induction of autophagy and inhibition of topoisomerase activity (Preet et al., 2012, Mohapatra et al., 2012). We have shown that QC inhibits WNT-β catenin cascade by inducing GSK3β and APC in breast cancer cells (Preet et al., 2013). Recently, we have also shown that nanoformulated QC (NQC) inhibits the HH-GLI cascade by interrupting the binding of GLI1 to GLI1-DNA complexes and activating GSK3β. Although GSK3β is not the direct component of canonical HH-GLI cascade but it modulates HH-GLI signalling non-canonically. Report also suggests that GSK3β activation leads to apoptosis in MCF-7 cells (Alao et al., 2006). As GSK3β negatively regulate both the WNT-β catenin and HH-GLI cascade, this could be an attractive target for anti-CSC drug design.

Using OCSCs as model system and CSCs derived from patient sample we have here shown that NQC caused the CSCs death by modulation of β catenin and GLI1 interaction through GSK3β.

Oral cancer cell lines H-357 and SCC-25 were grown in DMEM-F12 (50:50, v/v) medium supplemented with 10% FBS, 1% antibiotic (100 U/mL) penicillin, 10 mg/mL of streptomycin in 0.9% normal saline), and 0.5 mg/mL of hydrocortisone. QC, PVA and LiCl were purchased from Sigma Chemical Ltd. (St Louis, MO, USA). GSK3βsiRNA (r) and scramble si RNA were procured from Santa Cruz Biotechnology (CA, USA). Primers were purchased from Integrated DNA Technologies, USA. Anti-Oct-4 (ab18976), anti-Sox-2 (ab137385), anti-Nanog (ab80892) and anti-HA (# ab18181) were procured from Abcam (Cambridge, United Kingdom) and used in 1:2000 dilutions and washed three times for 3 min followed by primary and secondary antibody incubation. Anti-GSK3β (#9315), anti-p GSK3β (ser 9) (#9331), anti-GLI1 (#92611), anti-β catenin (# 9562), anti-CK (#2655), anti-Cyclin D1 (# 2978), anti-C-myc (# 9402) were procured from Cell Signalling Technology (MA, USA) and used in 1:1000 dilutions and washed three times for three minutes after primary antibody incubation and three times for five minutes after secondary antibody incubation. Anti-ALDH1 (ab52492) used for flow was procured from Abcam (Cambridge, United Kingdom) and used as 1:500 dilutions. CD 133 (c9493) was procured from Sigma Chemical Ltd. (St Louis, MO, USA) and used in a dilution of 1:500. FITC anti-human CD117 (c-kit) antibody was purchased from Biolegend, San Diego, CA, USA and used in 1:500 dilutions.

NQC was prepared from QC by simple oil immersion solvent precipitation techniques and characterized as per the protocol described earlier (Nayak et al., 2016). The Nanoformulation was lyophilized and stored in − 80 °C. The powder was dissolved in water (w/v) for making desired solution for experimentation. Formulated nanoparticle showed UV–visible spectra at 420 nm having spherical 100 nm diameter with positive zeta potential + 2.380 ± 0.920 mV and a face centred cubic structure.

Oral cancer patient samples were obtained from Acharya Harihar Regional Cancer Centre (AHRCC), Cuttack, Odisha, India as per the ethical guidelines of the hospital. All the experiments of human sample were performed after ethical approval from the hospital. Tumors were cut into small pieces and then incubated with collagenase III and dispase cocktail at 37 °C for 2 h with constant rotation. To get single cell suspension, the cells were filtered sequentially through 100 μm and 40 μm cell strainer and then grown in culture. The oral cancer cells H-357 and SSC-25 were grown. 1 × 105 cells (both patient derived primary and oral cancer cells) were incubated with specific oral CSCs marker CD 117 (C kit) and then sorted by FACS Aria II (Becton Dickinson Biosciences, San Jose, USA). Sorted cells were grown and used for experimentation. CSCs properties of the cells were measured by monitoring the expressions of representative markers of CSCs such as ALDH1, CD133, OCT4, SOX2, and NANOG using western blot or ELISA.

The anchorage-dependent viability of different OCSCs and patient derived primary OCSCs after NQC exposure were measured using a colorimetric based MTT cell viability assay according to the protocol referred earlier (Nayak et al., 2016). In brief, 8000–10,000 cells were seeded in triplicate and grown to 60–70% confluence prior to treatment with NQC for 48 h and then MTT reagent was added for the formation of formazan crystal. The crystal was dissolved by detergent and intensity of colour was measured at 570 nm using spectrophotometer (Berthold, Germany).

1 × 105 seeded H-357-CSC were treated with increasing concentrations of NQC for 48 h. Total RNA was isolated using GeneJET RNA purification Kit (Cat No#K0732, Fermentas, USA) and c-DNA was synthesized using revert AID first strand cDNA synthesis kit (CAT#K1622, Fermentas, USA). Amplification was done by PCR using the primer (Forward: 5′-GGAACTCCAACAAGGGAGCA-3′) and (Reverse: 5′-TTCGGGGTCGGAAGACCTTA-3′). Samples were separated on 1% agarose gel and images were captured under UV.

To study the co-localization of GLI1 and β catenin, an immunocytochemistry was carried out. Briefly, H-357-CSCs were seeded onto cover slips, and treated with varied concentrations of NQC prior to fixing with acetone:methanol (1:1). After blocking, cells were incubated either with anti-GLI1 or anti-β catenin antibody. Then secondary anti-rabbit-TRITC (GLI1) and anti-rabbit-FITC (β catenin) was added. After washing with 1 × PBS, immunoflourescence was detected using fluorescence microscope (Olympus BX61, USA). Co-localization of GLI1 (TRITC) and β catenin (FITC) was noticed by yellow colour formation (indicted by arrow) after merging the florescence for GLI1 (red) and β catenin (green). Experiments were carried out thrice and representative images have been provided.

The matrigel invasion assay was performed using a 24 well trans well plate (#3422, Corning, NY, USA) with a pore size of 8 μm; the inserts were coated with 20 μl of matrigel (356234, BD Biosciences, CA, USA) according to protocol described earlier (Siddharth et al., 2016). 3 × 105 cells were resuspended in 100 μl of media and seeded either on uncoated inserts (migration) or on the matrigel coated inserts (invasion). Complete media was added to the lower chamber, incubated for 24 h. Non-invaded cells were removed, and invaded cells were fixed with 4% paraformaldehyde, stained with DAPI and counted at 40 × under the fluorescence microscope (Nikon, Tokyo, Japan). The data were expressed as % invasion against cell types.

% invasion was calculated using the following formula%Invasion=Number of cells invaded the matrigel coated inserts towards the complete media/Number of cells migrated the uncoated inserts towards the complete media×100.

Whole cell lysates of CSCs, patient derived primary cells and tissue lysates were prepared using RIPA lysis buffer and processed for western blot analysis using the antibody specific manufactures protocol. The band intensity of each lane was measured using a UVP GelDoc-ItR 310 Imaging system (UVP, Cambridge, UK) and compared with control which was represented as numerical values above each panel.

GSK3β siRNA (r) (sc-270460) along with scrambled were procured from Santa Cruz Biotechnology. Briefly SCC-25-CSC and H-357-CSC were grown on 100 mm cell culture discs up to 70% confluence and transfection was carried out using Lipofectamine 2000® reagent as per the protocol described earlier (Nayak et al., 2016). Silenced cells were further grown and treated with NQC as mentioned above. Cells were harvested and GSK3β level was monitored by western blot.

To study the protein–protein interaction between GLI1 and β catenin, GSK3β and GLI1 and β catenin an immunoprecipitation assay was performed according to the protocol referred earlier (Das et al., 2014). 70–80% confluence cells were treated with different concentrations with NQC for 48 h prior to harvest. After washing pellet with 1XPBS cellular lysates were made using RIPA lysis buffer. BSA-blocked protein-Sepharose 4B was incubated with IgG or anti-GLI1, anti-β catenin, anti-GSK3β for 4 h at 4 °C. After washing with PBS 150 μg of total cellular lysate was added and incubated for overnight. Non-specifically bound proteins were removed by washing sequentially with lysis buffer, 0.5 N LiCl, and with 1 × PBS. Beads were then suspended in lamelli buffer, and separated on 10% SDS-PAGE and then probed with specific antibody.

Expression of Caspase 3 in cytoplasm after NQC treatment in H-357-CSCs was measured by immunocytochemistry. Briefly, NQC treated H-357-CSCs after fixing with acetone:methanol processed for immunocytochemistry as described in the protocol (Das et al., 2017).

Annexin V-FITC/PI dual staining is used to measure apoptosis as per the protocol described earlier (Das et al., 2017). Briefly 1 × 105 H-357-CSCs were seeded and grown up to 60% confluency. Cells were treated with different concentrations of NQC for 48 h. Then cells were stained with Annexin V/FITC-PI prior to FACS. Approximately 10,000 cells per sample were acquired using FITC/PE channel and analysed through FACS Diva software.

Expressions of CSC markers were measured by FACS as per the protocol described earlier (Siddharth et al., 2016). Cells were incubated with specific antibody and analysed by FACS. At least 10,000 cells/samples were analysed by FACS Diva software.

Expressions of CSC markers were also measured using ELISA as per the protocol described earlier (Nayak et al., 2016). Antigen coated plates were incubated with primary (anti-Oct4, ant-Sox2 and anti-Nanog) antibody and then HRP conjugated secondary antibody. Absorbance was taken at 450 nm in ELISA reader (Berthold, Germany) after addition of substrate solution i.e. 2, 2′-azinobis-(3-ethylbenzthiazoline-6-sulphonic acid).

To measure the promoter activity of GLI1, and TCF/LEF (a WNT-β catenin transcription factor) a luciferase based reporter assay was performed according to the protocol described earlier (Preet et al., 2013, Nayak et al., 2016). Briefly 1 × 106 cells were grown in 6 well tissue culture plates and grown up to 70% confluency prior to transient transfection with PGL2-LUC-GLI1 and TOPFLASH/FOP FLASH plasmid and then cells were treated with NQC for 48 h. Then luciferase activity was measured using DLR luciferase assay instrument (Berthold, Germany).

GSK3β was over expressed by transient transfection of GSK3β plasmid as per the protocol described earlier (Nayak et al., 2016). In brief, 60–70% confluent GSK3β-KD H357-CSCs and SCC-25-CSCs in 6 well plates were transiently transfected with PC DNA 3.1 HA GSK3βWT and PC DNA 3.1 HA GSK3βS9A (a kind gift from Dr. Ajay Rana, department of internal medicine, cardiovascular and cancer research institute, Texas) and then treated with varied concentrations of NQC. GSK3β expression was determined by western blot.

The statistical analysis was performed using Graph Pad Prism version 5 software, USA. Results represented as mean ± SEM. of 3 independent experiments. The data were analysed by repeated measure of one-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparison test. In transfection assay *** is compared to untransfected control and ### is compared to *** (transfected control). Statistical significance of difference in the central tendencies and #, ## and ### is compared to *** and designated as *p < 0.05, **p < 0.005 and ***p < 0.001. #p < 0.05, ##p < 0.005 and ###p < 0.001.

Section snippets

Isolation and characterization of OCSCs from H-357 and SCC-25 oral cancer cells

At first, the highly enriched CSCs were isolated by sorting the H-357 and SCC-25 oral cancer cells using CD117 (candidate stem cell marker for oral cancer stem cells) by FACS. Approximately, 7.3% and 5.6% CD-117 positive cells were noted in H-357 and SCC-25, respectively after sorting. These sorted cells were grown in cell culture and termed H-357-CSCs and SCC-25-CSCs and used for further experimentation (Fig. 1A). To confirm the stemness of these cells, other representative CSC markers have

Discussion

WNT-β catenin and HH-GLI signalling cascade plays vita role in embryogenesis, stem cell growth and maintenance, tumorigenesis, metastasis and angiogenesis. They interact in arrays of cancer and significance of these signalling cascades has been well documented in oral carcinogenesis (Wang et al., 2012, Schneider et al., 2011). Although researchers all over the globe are trying to develop potential therapeutic agents by targeting these pathways but hitherto no successful agents are in clinic.

Conflict of interest

None declared.

Author contribution

Most of the work carried out by AN. SS, SD, DN, CS performed some experiments and analysis the data. CNK conceived the idea overall supervise the work and wrote the MS.

Acknowledgement

A.N., S.S. and S.D. are thankful to ICMR and DST, Government of India, respectively, for providing Senior Research Fellowship. The part of the work is supported by ICMR (Ref # 35/22/2012-BMS), Govt of India, funded project of CNK.

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