Involvement of hedgehog signaling in all-trans retinoic acid-mediated suppression of colon cancer

Abstract

All-trans retinoic acid (ATRA) exerts tumor-inhibitory effects on acute leukemia and certain types of solid tumors. This study was designed to evaluate the mechanism on ATRA-mediated suppression of colon cancer based on the sonic hedgehog (Shh) signaling pathway.

Methods: Normal intestinal epithelial cells and three colon cancer cell lines were studied to evaluate the inhibitory effect of ATRA on tumor cell activity. The inhibitory effect of ATRA on colon cancer was evaluated by cell invasion, migration, and apoptosis of HCT116 cells. Retinoic acid receptor (RAR)- and Shh-related protein expression was assessed.

Results: ATRA administration inhibited the activity of three different colon cancer lines, but did not inhibit the activity of normal intestinal epithelial cells. Administration of ATRA induced apoptosis and restricted invasion and migration of HCT116 colon cancer cells. Administration of ATRA also increased expression of RAR and transmembrane receptor patched 1 (Ptch1), and decreased expression of the smoothened (Smo) and glioma-associated oncogene homolog1 (Gli-1). RARα and RARβ agonists inhibited Shh signaling, and the mediating effect of ATRA on Shh signaling was abolished by RARα or RARβ antagonists. The combination of purmorphamine (Smo agonist) and ATRA partially abolished the inhibitory effect of ATRA on the proliferation of colon cancer cells. In vivo studies showed that ATRA inhibited tumor growth, which was accompanied by down-regulation of the Shh signaling pathway.

Conclusions: ATRA inhibits the growth of colon cancer by downregulating the Shh pathway, which further verifies the anticancer activity of ATRA.

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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 Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- Pancreatic Adenocarcinoma: clinical records on 17 patients treated with Di Bella's Method;

- The Di Bella Method Increases by the 30% the survival rate for Pancreas tumors and for this reason should be proposed as first line therapy for this type of cancer;

- The Di Bella Method (DBM) in the treatment of prostate cancer: a preliminary retrospective study of 16 patients and a review of the literature;

- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- 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;

- A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method: A rationale and effectiveness;

- 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;

- 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;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- Neuroblastoma: Complete objective response to biological treatment;

- Oesophageal squamocellular carcinoma: a complete and objective response.