Acetylshikonin suppresses invasion of Porphyromonas�gingivalis‑infected YD10B oral cancer cells by modulating the interleukin-8/matrix metalloproteinase axis

Abstract

The development of pharmaceutical agents possessing anti-invasive and anti-metastatic abilities, as well as apoptotic activity, is important in decreasing the incidence and recurrence of oral cancer. Cancer cells are known to acquire invasiveness not only through epigenetic changes, but also from inflammatory stimuli within the tumor microenvironment. Accordingly, the identification of agents that can suppress the inflammation-promoted invasiveness of cancer cells may be important in treating cancer and improving the prognosis of patients with cancer. Acetylshikonin, a flavonoid with anti-inflammatory activity, inhibits proliferation and induces apoptosis of oral cancer cells. In the present study, the anti-invasive effect of acetylshikonin on YD10B oral cancer cells infected with Porphyromonas gingivalis, a major pathogen of chronic periodontitis, and the mechanisms involved were investigated. Firstly, we examined whether P. gingivalis infection increased the invasiveness of YD10B cells. Results suggested that YD10B oral cancer cells become more aggressive when they are infected with P. gingivalis. Secondly, acetylshikonin significantly inhibited the invasion of P. gingivalis-infected YD10B cells by suppressing IL-8 release and IL-8-dependent MMP release. These data suggest that acetylshikonin may be a useful preventive and therapeutic candidate for oral cancer that is chronically infected with periodontal pathogens.

Role of Porphyromonas gingivalis in oral squamous cell carcinoma development: A systematic review

“…These infected cells were less resistant to electrostimulation than non‐infected cells, showing a pattern more fibroblastic, with higher migratory invasive capacity. Cho et al reported similar findings in OSCC cells (YD10B line) infected with P gingivalis . Cell lost polygonal shape, and there was an overexpression of vimentin, α‐SMA, and transcription factors, Snail, Slug, and Twist, together with a downregulation of CK13.…”

“…Studies were classified into three main groups according to oral specimen origins. In the first one, three studies (18.75%) used epithelial cells from human samples (Table ); in the second, three studies (18.75%) evaluated murine models (Table ); and in the last one, 11 studies (62.5%) were developed in pre‐established cell lines (Table ).…”

“…Alterations of these cell pathways reduce epithelial expression of cancerous cells. These changes appear in healthy gingival epithelial cells, both from human biopsies and from pre‐established cell lines, as well as in OSCC cells infected with P gingivalis . Sztukowska et al were the only authors to obtain these results in an in vivo OSCC and healthy in vitro.…”

“…In a second one (promotion), tissue growth and cancer could develop throughout overexpression of receptors and growth factors, cytokines, extracellular matrix destruction, angiogenesis, etc In the last one (progression), malignant cells invade local or distant tissues, while molecular alterations continue to carry on. Steps of oral carcinogenesis in which P gingivalis play an important role (Figure ) are epithelial‐mesenchymal transition of oral epithelial cells, neoplastic cell proliferation, and tumor cell invasiveness …”

“…Epithelial‐mesenchymal transformation (EMT) determines a change of oral epithelial cells into a mesenchymal phenotype, and a loss of their adhesion properties . In this sense, P gingivalis may become an activation factor for ZEB1, or Snail/ Slug/ Twist transcription factors . Alterations of these cell pathways reduce epithelial expression of cancerous cells.…”