Activation of the FAK/PI3K pathway is crucial for AURKA-induced epithelial-mesenchymal transition in laryngeal cancer

  • Authors:
    • Liyun Yang
    • Quan Zhou
    • Xuehua Chen
    • Liping Su
    • Bingya Liu
    • Hao Zhang
  • View Affiliations

  • Published online on: June 13, 2016     https://doi.org/10.3892/or.2016.4872
  • Pages: 819-826
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Abstract

Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors, and the main cause of death is metastasis. Overexpression of aurora kinase A (AURKA) plays an important role in the metastasis of LSCC. However, the mechanism by which AURKA promotes the metastasis of LSCC is poorly understood. Recent accumulating evidence indicates that epithelial-mesenchymal transition (EMT) may be one of the mechanisms of tumor metastasis. In the present study, we studied whether AURKA may induce EMT to promote the metastasis of LSCC. CCK-8 and plate colony-formation assays were carried out to show that AURKA significantly promoted the proliferation of Hep2 cells. Immunofluorescence staining and western blotting showed that EMT-related proteins changed in a time-dependent manner along with the alteration of AURKA, with decreased expression of N-cadherin, vimentin and slug and increased expression of E-cadherin. Additionally, downregulation of the expression of AURKA inhibited FAK/PI3K pathway activity. Inhibition of the FAK/PI3K pathway caused less mesenchymal-like characteristics and reduced the mobility, migration and invasion of Hep2 cells. In conclusion, AURKA may induce EMT to promote metastasis via activation of the FAK/PI3K pathway in LSCC. Those regulatory factors may present new diagnostic biomarkers and potential therapeutic targets for LSCC.

Introduction

Laryngeal squamous cell carcinoma (LSCC), arises from the larynx epithelium and is one of the most common head and neck squamous cell carcinomas (HNSCCs) with a high rate of metastasis and a poor prognosis (1,2). Currently, LSCC accounts for almost 2% of all malignancies worldwide (3,4). Although recent treatment outcomes are improved, patients still have a poor prognosis with a 5-year survival rate of ~60% (5). The main cause of death is cancer metastasis (6) and the intrinsic microenvironment of tumor cells has an important role in tumor metastasis (7). Therefore, a better understanding of the underlying molecular metastasis-related mechanisms of LSCC is essential for developing effective therapeutic strategies to improve the survival rate and quality of life of these patients.

Aurora kinase A (AURKA), a homologue of aurora/Ipl1-related kinase, is located at chromosome 20q13.2 (8). It is an oncogene that causes various epithelial malignant tumors, including pancreatic (9), ovarian (10), colorectal (11) and prostate cancer (12). We previously reported that the expression of AURKA was elevated in human LSCC and promoted the metastasis of LSCC (13,14). However, the underlying mechanism by which AURKA enhances the metastasis of LSCC is still poorly understood.

Recent accumulating evidence indicates that the occurrence of epithelial-mesenchymal transition (EMT) may be the principal mechanism of cancer metastasis, including bladder (15), colorectal (16), pancreatic (17), breast (18), oral (19), thyroid (20) and prostate cancer (21), and LSCC (22). EMT is the process by which epithelial cells de-differentiate into mesenchymal-like derivatives (23). During the process, epithelial cells acquire the characteristics of mesenchymal cells, such as lack of polarization, increased motility and invasion, decreased cell-cell junctions and chemotherapeutic resistance (2426). Recently, D'Assoro et al reported that AURKA induced EMT to promote distant metastasis in breast cancer (27). This indicates an association between AURKA and EMT and cancer metastasis.

Therefore, in the present study, we investigated whether AURKA is involved in EMT to promote the metastasis of LSCC. The epithelial-related protein E-cadherin and the mesenchymal-related proteins, N-cadherin, vimentin and slug, were investigated either in AURKA-downregulated or parental Hep2 cells. Effects of inhibition of the FAK/PI3K pathway on the mesenchymal-like characteristics and cellular mobility, migration and invasion ability were also studied in these Hep2 cells.

Materials and methods

Cell cultures

The human laryngeal cancer Hep2 cell line (Hep2 cells) was obtained from Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences. Hep2 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum (FBS) (both from Gibco, Bedford, MA, USA) and 1% penicillin/streptomycin at 37°C under 5% CO2.

Cell proliferation assay

Cell proliferation was measured with the CCK-8 assay kit (Gibco). Briefly, a total density of 3×103 Hep2 cells/well, growing in logarithmic phase, in 100 µl of DMEM were plated into the 96-well plates. Then, 10 µl of CCK-8 was added into every well at the specific time points. After culture for 2 h at 37°C under 5% CO2, OD450 absorbance values were monitored. In the present study, the proliferation of T-Hep2 cells following treatment with the selective inhibitor of AURKA (VX680) (Selleck Chemicals, Houston, TX, USA), which was dissolved in dimethyl sulfoxide (DMSO), was measured at 0, 24 and 48 h for 2 days.

Plate colony-formation assay

Hep2 cells treated with VX680 for 48 h were the experimental group and the cells treated with DMSO or without any treatment were considered the controls. Cells at a density of 2×103 were layered into 6-well plates. After culture for 2 weeks with DMEM containing 10% FBS, the cells were washed with phosphate-buffered saline (PBS) 3 times and fixed with crystal violet for 30 min at room temperature. The formed colonies were counted in every well.

Immunofluorescence staining

Hep2 cells treated with VX680 for 48 h or without any treatment, at the density of 5×104, were seeded into Millicell® EZ Slides (Millipore, Bedford, MA, USA). The cells were fixed with 4% paraformaldehyde (PFA) for 30 min when they adhered to the wall of the slides. Then, the slides were rinsed 3 times with 1X PBS for 5 min each time, followed by blocking with primary cocktail (Cell Signaling Technology, Danvers, MA, USA) (diluted 1:100 as indicated on the datasheet in antibody dilution buffer) to examine the expression of EMT markers, vimentin and E-cadherin. Following overnight incubation at 4°C, the blocking solution was aspirated and the slides were washed 3 times with 1X PBS for 5 min each time and were then incubated with Alexa Fluor® 555 and Alexa Flour® 488 (Cell Signaling Technology) (diluted 1:100 as indicated on the datasheet in antibody dilution buffer) for 1 h at room temperature in the dark. Then, the slides were rinsed 3 times with 1X PBS for 5 min each. For immunofluorescence staining of p-AURKA (anti-p-AURKA; 1:100; Cell Signaling Technology), blocking with 5% BSA in PBS containing 0.05% Triton for 1 h at room temperature was the only difference in the protocol. Vimentin and E-cadherin were analyzed using fluorescence microscopy magnification, ×10 (U-ULS100HG; Olympus Optical Co., Ltd., Tokyo, Japan) (magnification, ×10).

Western blot analysis

Hep2 cells, treated with VX680, the inhibitor of FAK (TAE226), and the inhibitor of PI3K (omipalisib) (both from Selleck Chemicals), respectively, were lysed with RIPA buffer containing 1% protease inhibitor cocktail (100:1) and quantified by the BCA protein assay kit (all from Pierce, Rockford, IL, USA) according to the manufacturer's instructions. Harvested proteins were separated with 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) for 2 h and transferred onto polyvinylidene difluoride (PVDF) membranes (Millipore) for 2 h. Then, the membranes were blocked with 5% non-fat milk dissolved in 1X TBST (150 mM NaCl, 0.05% Tween-20, 10 mM Tris-HCl, pH 8.0) for 2 h, and incubated with the primary antibodies at 4°C overnight including anti-E-cadherin (1:2,000), anti-N-cadherin (1:2,000), anti-vimentin (1:2,000), anti-slug (1:2,000) (all from Proteintech Group, Inc., Rosemont, IL, USA), anti-p-AURKA (1:2,000), anti-AURKA (1:2,000), anti-FAK (1:2,000), anti-p-FAK (Tyr397, 1:2,000) (all from Cell Signaling Technology), anti-PI3K (1:2,000), anti-p-PI3K (1:2,000) and GAPDH (1:5,000) (all from Abcam). After overnight incubation, the PVDF membranes were washed with 1X TBST 3 times and incubated with a secondary antibody (1:5,000; Cell Signaling Technology) for 2 h at room temperature. Lastly, the membranes were detected with an enhanced chemiluminescence detection system (Amersham Biosciences, Piscataway, NJ, USA).

Wound healing assay

Hep2 cells treated with TAE226 and omipalisib were considered the experimental groups, and groups treated with DMSO or without any treatment were the control groups. Hep2 cells at a density of 1×106 cell/well were seeded into 6-well plates. After overnight culture, the Hep2 cells were scratched with 20-µl pipette tips to form straight lines. The floating cells were removed using 1X PBS 3 times. Finally, the wound lines were photographed at 0, 24 and 48 h at a magnification of ×2.

Cell migration and invasion assays

A density of 2×105 cell/well treated with TAE226, omipalisib, DMSO or without any treatment suspended in 200 µl of serum-free DMEM were placed into the top of Transwell chambers (Corning, Tewksbury, MA, USA) and the lower chambers were filled with 600 µl of DMEM with 10% FBS. After overnight culture, non-migratory Hep2 cells were removed with a cotton swab from the top surface of the chamber and the lower filter of the chamber was stained with crystal violet solution for 30 min at 37°C. Then, the migratory Hep2 cells were photographed using microscopy at magnification, ×20. Briefly, the experimental produces of the cell invasion and the cell migration assays were identical except that BD Matrigel™ (Becton-Dickinson Labware, Bedford, MA, USA) covered the membrane of the top chamber.

Statistical analysis

Data of all experiments were analyzed by GraphPad Prism 6 software (GraphPad, San Diego, CA, USA) and are shown as mean ± SD. The Student's t-test was performed to assess the differences between experimental groups and controls. The level of significance was set at P<0.05, and a high level of significance was set at P<0.01.

Results

Inhibition of AURKA with VX680 reduces the proliferation of Hep2 cells

Our previous study showed that AURKA was overexpressed in Hep2 cells and promoted the metastasis of LSCC (13,14). We downregulated AURKA with VX680 (80 nm/ml) (28), a selective inhibitor of AURKA, in the Hep2 cells for 24 and 48 h (Hep2/VX680). Hep2 cells treated with DMSO (Hep2/ctrl) and without any treatment (Hep2/parental) were the control groups. The results of the CCK-8 assay showed less proliferation in the Hep2/VX680 cells compared with the Hep2/ctrl and Hep2/parental cells (P<0.05; Fig. 1A). The plate colony-formation assay showed parallel results in the Hep2/VX680 (404±18.95), Hep2/ctrl (601±16.74) and Hep2/parental cells (607±24.11) (P<0.01; Fig. 1B and C). These results indicated that AURKA significantly promoted cell proliferation and that VX680 effectively reduced the function of AURKA.

Downregulation of AURKA causes less mesenchymal-like characteristics in Hep2 cells

To investigate whether AURKA is involved in EMT to promote the metastasis of LSCC, the EMT-related proteins E-cadherin, N-cadherin, vimentin and slug were assessed in the Hep2 cells treated with VX680 at specific times. The results of immunofluorescence staining showed that the expression of p-AURKA and vimentin in the Hep2 cells was lower, while the expression of E-cadherin was higher when compared with these levels in the control group (Fig. 2A). Subsequently, the results of western blotting also revealed that the expression of p-AURKA was decreased almost 3-fold (P<0.01; Fig. 2B and C) and the EMT-related protein levels were altered in a time-dependent manner along with the alteration of AURKA. Expression of E-cadherin was increased and expression of N-cadherin, vimentin and slug was decreased (Fig. 2B and C). All of the aforementioned observations indicated that AURKA may induce EMT to promote the metastasis of LSCC.

AURKA promotes the metastasis of LSCC by enhancing phosphorylation of the FAK/PI3K pathway

Given that the FAK pathway is regarded as a regulatory factor in tumor metastasis (2931) and FAK is involved in PI3K-promoted EMT in lung cancer (32), we aimed to demonstrate that AURKA regulates those factors to induce EMT. As expected, the expression of p-FAK (Tyr397) and p-PI3K was reduced following the diminution of p-AURKA in the Hep2 cells (P<0.01; Fig. 3A and B), which demonstrated that FAK and PI3K were regulated by AURKA and played a key role in contributing to the tumorigenesis of LSCC.

Inhibition of the FAK/PI3K pathway causes less mesenchymal-like characteristics

To explore whether the FAK/PI3K pathway plays a key role in the induction of EMT in LSCC, we utilized the FAK inhibitor TAE226 (2.1 µM/ml) (33), and PI3K inhibitor omipalisib (500 nm/ml) (34) dissolved in DMSO. Treatment with TAE226 altered the EMT-related proteins in a time-dependent manner. The level of E-cadherin was increased, while N-cadherin, vimentin and slug were decreased, indicating that FAK caused more mesenchymal-like characteristics (Fig. 4A and B). p-AURKA, AURKA, p-FAK (Tyr397), FAK, p-PI3K and PI3K in the Hep2/TAE226 cells were also examined. The expression of p-FAK (Tyr397) was nearly decreased 2-fold after treatment with TAE226 for 24 h (P<0.05; Fig. 4C and D). In addition, the expression of p-PI3K was decreased (P<0.01; Fig. 4C and D), whereas p-AURKA, AURKA, FAK and PI3K were not changed, indicating that FAK is a downstream factor of AURKA.

EMT-related proteins were also inhibited in the Hep2/omipalisib cells. These observations showed that E-cadherin was increased, while N-cadherin, vimentin and slug were decreased, which also demonstrated that inhibition of PI3K caused less mesenchymal-like characteristics (Fig. 4E and F). Moreover, p-AURKA, AURKA, p-FAK (Tyr397), FAK, p-PI3K and PI3K were assessed after using omipalisib for 0, 6 and 12 h. From the results of the western blotting, p-PI3K was markedly decreased (P<0.01; Fig. 4G and H), whereas p-AURKA, AURKA, p-FAK (Tyr397), FAK and PI3K were not changed, which illustratied that PI3K is a downstream factor of AURKA/FAK (Fig. 4G and H).

Inhibition of the FAK/PI3K pathway decreases cellular mobility, migration and invasion

To further demonstrate that activation of the FAK/PI3K pathway may be crucial for AURKA-induced EMT in LSCC metastasis, wound healing, migration and invasion assays were performed. We down-regulated FAK and PI3K with TAE226 (Hep2/TAE226) and omipalisib (Hep2/omipalisib), respectively. Similarly, Hep2 cells treated with DMSO (Hep2/ctrl) and without any treatment (Hep2/parental) were considered the control groups. First the wound was scratched and observed for 0, 24 and 48 h. The results showed that Hep2/TAE226 and Hep2/omipalisib cells moved slightly, while Hep2/ctrl and Hep2/parental cells almost reached the middle of the scratch, indicating that FAK and PI3K caused more mesenchymal-like characteristics and markedly promoted Hep2 cell mobility (P<0.05; Fig. 5A and B).

Similarly, the results of the migration assay indicated that the numbers of Hep2/TAE226 (101±7.23) and Hep2/omipalisib cells (101±12.7) migrating through the Transwell chamber were significantly less than these numbers in the Hep2/parental (203±8.76) and Hep2/ctrl cells (203±13.33). The invasion assay also showed parallel results with Hep2/TAE226 (88±4.10), Hep2/omipalisib (105±3.93), Hep2/parental (130±3.46), Hep2/ctrl cells (135±2.89) (Fig. 5C and D). These observations indirectly illustrated that FAK and PI3K acquired more mesenchymal-like characteristics and increased mobility, migration and invasion.

Discussion

Cancer metastasis accounts for the majority of tumor-related deaths worldwide. Understanding the potential mechanism of metastasis has been long recognized as an essential target in the treatment of cancer. However, the precise molecular and cellular metastasis-related mechanisms are poorly understood (35). Based on our previous research showing that AURKA plays a key role in the tumorigenesis and metastasis of LSCC in vitro (13) and in vivo (14), as well as growing evidence suggesting that EMT may be the principal mechanism of cancer metastasis (1522), we explored the correlation between AURKA and EMT in contributing to the metastasis of LSCC. To the best of our knowledge, no previous study has been reported dealing with this domain in LSCC.

AURKA, a member of the evolutionarily conserved aurora serine/threonine kinase family, controls cell cycle (36) by centrosome maturation, mitotic entry, centrosome separation, bipolar spindle assembly, chromosome alignment, cytokinesis and mitotic exit (37). Dysfunctional regulation during mitosis leads to genetic instability and tumorigenesis. In the present study, results of the CCK-8 and plate colony-formation assays showed that VX680 inhibited the proliferation of Hep2 cells, and that AURKA is a tumor-inducing gene in LSCC. Notably, mesenchymal-related proteins, N-cadherin, vimentin and slug, which endow cells with more migratory and invasive properties (26), were decreased in a time-dependent manner following the reduction of AURKA, while the epithelial-related protein E-cadherin was negatively correlated with AURKA in the Hep2 cells. According to the aforementioned observations, we demonstrated that AURKA may promote the metastasis of LSCC by inducing EMT and may be regarded as a mesenchymal marker.

In addition, the process of metastasis involves numerous potential signaling pathways. Niu et al stated that EMT could be correlated with the p38 MAPK/PI3K/Akt/mTOR pathway to promote osteosarcoma metastasis (36), Kuo et al indicated that EMT involves the NF-κB/ZEB1 pathway to promote lung cancer cell migration and invasion (38). The FAK-mediated PI3K/AKT pathway acts through EMT to enhance lung cancer metastasis (31). In the present study, down regulation of the expression of AURKA reduced the expression of FAK and PI3K indicating that AURKA may act on FAK and PI3K to facilitate tumor metastasis. Subsequently, TAE226 was applied to block the expression of p-FAK (Tyr397). Notably, the expression of p-PI3K was also decreased, whereas p-AURKA, AURKA, FAK and PI3K were not altered, indicating that FAK is the downstream factor of AURKA. p-PI3K was markedly decreased after treatment with omipalisib for 12 h; inversely p-AURKA, AURKA, p-FAK (Tyr397), FAK and PI3K were not altered, indicating that PI3K is a downstream factor of AURKA/FAK. Finally, inhibition of FAK or PI3K altered the expression of EMT markers which was the same as the treatment of VX680 and allowed mesenchymal cells to acquire the characteristics of epithelial cells to reduce mobility, migration and invasion in Hep2 cells. All of these results imply that the FAK/PI3K pathway is under the regulation of AURKA to promote the process of EMT and enhance the metastasis of LSCC.

The present study suggests that VX680, TAE226 and omipalisib, which are inhibitors and implicated in the AURKA/FAK/PI3K signaling pathway, should not only be considered for single use but also for combination therapy in the treatment of patients with LSCC. Certainly, various doses and schedules of targeted therapeutic drugs should be examined in clinical trials to ensure the effectiveness and safety of LSCC therapy. Taken together, our results demonstrated that AURKA may enhance metastasis by inducing EMT via the FAK/PI3K pathway in LSCC. In addition, in light of our observations of the therapeutic potential in laryngeal cancer, the AURKA/FAK/PI3K pathway may present new diagnostic biomarkers and potential therapeutic targets for LSCC.

Acknowledgments

The present study was supported by grants from the Science and Technology Commission of Shanghai Municipality (no. 12ZR1418700) and the Clinical Science and Technology Innovation Project of Shenkang Hospital Development Center (SHDC12015114).

Abbreviations:

LSCC

laryngeal squamous cell carcinoma

HNSCC

head and neck squamous cell carcinoma

AURKA

aurora kinase A

EMT

epithelial-mesenchymal transition

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Yang, L., Zhou, Q., Chen, X., Su, L., Liu, B., & Zhang, H. (2016). Activation of the FAK/PI3K pathway is crucial for AURKA-induced epithelial-mesenchymal transition in laryngeal cancer. Oncology Reports, 36, 819-826. https://doi.org/10.3892/or.2016.4872
MLA
Yang, L., Zhou, Q., Chen, X., Su, L., Liu, B., Zhang, H."Activation of the FAK/PI3K pathway is crucial for AURKA-induced epithelial-mesenchymal transition in laryngeal cancer". Oncology Reports 36.2 (2016): 819-826.
Chicago
Yang, L., Zhou, Q., Chen, X., Su, L., Liu, B., Zhang, H."Activation of the FAK/PI3K pathway is crucial for AURKA-induced epithelial-mesenchymal transition in laryngeal cancer". Oncology Reports 36, no. 2 (2016): 819-826. https://doi.org/10.3892/or.2016.4872