All-trans retinoic acid induces anti-tumor effects via STAT3 signaling inhibition in oral squamous cell carcinoma and oral dysplasia

Abstract

BACKGROUND: Oral squamous cell carcinoma (OSCC), which may arise from oral dysplasia, is one of the most prevalent cancers around the world. In recent years, all-trans retinoic acid (ATRA) has shown great potential in cancer treatment. However, the molecular mechanism for the anti-tumor effects of ATRA remains unclear.

MATERIALS AND METHODS: After treated with ATRA, inhibition of cell proliferation of OSCC and oral dysplasia cell lines, CAL27 and DOK, respectively, was analyzed by a Cell Counting Kit-8 (CCK8) assay. The cell cycle arrest, cell apoptosis induction, and PD-L1 expression level were measured by flow cytometry. A small molecular inhibitor was utilized to block STAT3 pathway, and the related proteins expression was measured by Western Blot.

RESULTS: The present study demonstrated that ATRA inhibited cell proliferation at 5-75 μmol/L, arrested cell cycle at S and G2-phase, induced apoptosis effect in OSCC, and oral dysplasia cell line, CAL27 and DOK, respectively. ATRA led to inhibition of p-STAT3, p-JAK2, increased the level of p-ERK, and significantly decreased the PD-L1 expression. Moreover, targeting STAT3 signaling increased (P < .001) the level of cleaved caspase-3 and effectively (P < .001) decreased the expression of cyclin A2 and PD-L1. The effect of ATRA on cell growth inhibition, apoptosis induction, and PD-L1 expression decrease was significantly (P < .05) enhanced after the STAT3 signaling blockade.

CONCLUSION: These findings suggested that ATRA-induced anti-tumor effects and downregulated PD-L1 expression via STAT3 signaling inhibition in both OSCC and oral dysplasia.

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See also:

- Official Web Site: The Di Bella Method;

- The Di Bella Method (A Fixed Part - All-Trans Retinoic Acid, Analogues and/or Derivatives - Approximately 60mg per day orally: 40mg per day Beta-Carotene/β-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate);

- All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives) - In vitro, review and in vivo publications;

- Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy;

- The Di Bella Method (A Fixed Part - Alpha tocopheryl acetate/Vitamin E, approximately 20 grams per day orally);

- Cancer and Vitamin E (analogues and/or derivatives) and cancer - In vitro, review and in vivo publications;

- The Di Bella Method (A Variable Part - Omega 3 Essential/Unsaturated Fatty Acids. From 1.5 grams up to 3.0 grams per day orally);

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

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- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide.