Honokiol inhibits bladder cancer cell invasion through repressing SRC-3 expression and epithelial-mesenchymal transition

Abstract

Abstract. Urinary bladder cancer (UBC) is one of the most common urological cancer types. Muscle invasive bladder cancer possesses high propensity for metastasis with poor prognosis. Honokiol is a lignan isolated from Magnolia officinalis with high bioavailability and potent anticancer effects. The results of the present study demonstrated that honokiol significantly inhibited UBC cell migration and invasion in a dose-dependent manner compared with the vehicle-treated control group. In addition, honokiol treatment suppressed epithelial-mesenchymal transition by induction of E-cadherin and repression of N-cadherin. Honokiol was capable of significantly downregulating the expression of cell invasion-associated genes, steroid receptor coactivator-3 (SRC-3), matrix metalloproteinase (MMP)-2 and Twist1. Notably, the inhibition of UBC cell invasion by honokiol was reversed by reintroduction of oncoprotein SRC-3 expression, with the restoration of MMP-2 and Twist1, and reduction of E-cadherin expression. Furthermore, the results of the luciferase assay confirmed that SRC-3 could regulate Twist1 promoter activity. Taken together, the results of the present study suggest that honokiol is a promising agent against UBC cell invasion via downregulation of SRC-3 and its target genes. IntroductionUrinary bladder cancer (UBC) is one of the most common types of malignant tumor in the United States, with an estimated 58,950 new cases and 11,820 UBC-associated mortalities in 2016 (1). Data between 2005 and 2011 in USA revealed that the 5-year survival rate for localized UBC was ~70%, whereas the rate for patients with UBC with distant lesions was ~5% (1). In China, bladder cancer prevalence ranks the 9th and the 2nd positions for the entire population, and people >65 years, respectively (2). However, current treatments, including chemotherapy and radiotherapy possess limited effects on muscle invasive bladder cancer (>stage 2). Therefore, studies investigating the underlying molecular mechanisms of UBC development and the development of efficacious therapeutic reagents for UBC, particularly for patients with invasive cancer are warranted.Steroid receptor coactivator-3 (SRC-3) and alias amplification in breast cancer 1 belong to the p160 steroid receptor coactivator family (3). Amplification and/or overexpression of SRC-3 have been implicated in steroid-targeted tissues, including in breast and prostate cancer (4-6), and in non-steroid-targeted tissues, including lung and bladder cancer (7-10). Accumulating evidence indicates that SRC-3 can activate steroid and non-steroid receptors. For example, SRC-3 serves as a co-activator for transcription factors ETS variant 4 (PEA3) and JunB proto-oncogene AP-1 transcription factor subunit, which leads to the upregulation of matrix metalloproteinase (MMP)-2, and -13 in androgen receptor-null PC3 prostate cancer cells (11). Furthermore, SRC-3 facilitates E2F transcription factor 1 (E2F1) to promote the proliferation of breast cancer cells (12). Previous studies, including our previous study,...

Honokiol: A Review of Its Anticancer Potential and Mechanisms

“…The expression of MMP-2 and MMP-9 were also found to be decreased in both honokiol-treated A549 and H1299 cells (NSCLC cell lines), consistent with the decreased nuclear accumulation of β-catenin as both MMP-2 and MMP-9 are the downstream targets of β-catenin [44,161,162]. In the J82 bladder cancer cell, honokiol repressed the expression of SRC-3, MMP-2, and Twist1 genes which were involved in cancer cell invasion [143].…”

“…Honokiol has been shown to block and inhibit EMT in many cancer cells such as breast cancer, melanoma, bladder cancer, human non-small cell lung cancer, and gastric cancer ( Table 1). Honokiol reduced steroid receptor coactivator-3 (SRC-3), matrix metalloproteinase (MMP)-2, and Twist1, preventing the invasion of urinary bladder cancer cells [108,143]. In addition, honokiol was also capable of inducing E-cadherin and repressing N-cadherin expression, thus inhibiting the EMT process in J82 bladder cancer cells [108,143].…”

“…Honokiol reduced steroid receptor coactivator-3 (SRC-3), matrix metalloproteinase (MMP)-2, and Twist1, preventing the invasion of urinary bladder cancer cells [108,143]. In addition, honokiol was also capable of inducing E-cadherin and repressing N-cadherin expression, thus inhibiting the EMT process in J82 bladder cancer cells [108,143]. In breast cancer cells, honokiol inhibits the recruitment of Stat3 on mesenchymal transcription factor Zeb1 promoter, resulting in decreased Zeb1 expression and nuclear translocation [144].…”

“…Various studies have reported that honokiol has the capability to suppress tumour metastasis in different types of cancer including breast cancer [40,148,154], non-small cell lung cancer [44,155] ovarian carcinoma cells [28], lung cancer [50], U251 human glioma, as well as U-87MG and T98G human glioblastoma cell [63,65,94], oral squamous cell carcinoma (OSCC) [26], bladder cancer cell [143], pancreatic cancer [58], renal cell carcinoma [156,157], and gastric cancer cells [113]. For instance, the percentage of invading urinary bladder cancer (UBC) cells was significantly reduced by 67% and 92% upon 2.4 µg/mL and 4.8 µg/mL of honokiol treatment, respectively [143]. Similarly, tumour cell migration was inhibited by 38-66% in A549 cells, by 37-62% in H1299 cells, 12% to 58% in H460 cells and 32% to 69% in H226 cells, in a concentration-dependent manner after treatment with honokiol [44].…”

“…Furthermore, honokiol also demonstrated an inhibitory effect on the expression of matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9 proteins, which play an essential role in the metastatic process of tumour cells, as well as the regulation of angiogenesis in the maintenance of tumour cell survivability [44,63,143]. MMPs are a group of extracellular matrix degrading enzymes that control various normal cellular processes, such as cell growth, differentiation, apoptosis, and migration [153].…”