<i>LDOC1</i> Suppresses Microbe-Induced Production of IL-1β in Human Normal and Cancerous Oral Cells through the PI3K/Akt/GSK-3β Axis

Abstract

Poor oral hygiene (POH) is associated with oral squamous cell carcinoma (OSCC). Oral microbes often proliferate due to POH. Array data show that LDOC1 plays a role in immunity against pathogens. We investigated whether LDOC1 regulates the production of oral microbe-induced IL-1β, an oncogenic proinflammatory cytokine in OSCC. We demonstrated the presence of Candida albicans (CA) in 11.3% of OSCC tissues (n = 80). CA and the oral bacterium Fusobacterium nucleatum stimulate higher levels of IL-1β secretion by LDOC1-deficient OSCC cells than by LDOC1-expressing oral cells. CA SC5314 increased OSCC incidence in 4-NQO (a synthetic tobacco carcinogen) and arecoline-cotreated mice. Loss and gain of LDOC1 function significantly increased and decreased, respectively, CA SC5314-induced IL-1β production in oral and OSCC cell lines. Mechanistic studies showed that LDOC1 deficiency increased active phosphorylated Akt upon CA SC5314 stimulation and subsequent inhibitory phosphorylation of GSK-3βS9 by activated Akt. PI3K and Akt inhibitors and expression of the constitutively active mutant GSK-3βS9A significantly reduced the CA SC5314-stimulated IL-1β production in LDOC1-deficient cells. These results indicate that the PI3K/Akt/pGSK-3β signaling pathway contributes to LDOC1-mediated inhibition of oral microbe-induced IL-1β production, suggesting that LDOC1 may determine the pathogenic role of oral microbes in POH-associated OSCC.

Keywords

• poor oral hygiene (POH)
• leucine-zipper downregulated in cancer 1 (<i>LDOC1</i>)
• <i>Candida albicans</i>
• interleukin 1beta (IL-1β)
• oral squamous cell carcinoma (OSCC)
• Protein Kinase B (PKB <i>Akt)</i>