Differential Regulation by Retinoic Acid and Calcium of Transglutaminases in Cultured Neoplastic and Normal Human Keratinocytes

Published on Wednesday, 23 June 2021


In five lines of cultured human squamous carcinoma cells, transglutaminase activity and envelope competence were highly sensitive to retinoic acid and calcium levels in the growth medium. In cells grown in low calcium medium, these measures of keratinocyte differentiation were reduced.

Retinoic acid suppressed envelope competence but total transglutaminase activity was markedly reduced, slightly affected, or greatly stimulated depending upon the cell line and whether the cells were grown in low calcium or 1.8 mM calcium-containing medium.

Examination by anion exchange chromatography of the transglutaminase activity in SCC-12B2 cultures showed that expression of the particulate form (type I) of the enzyme was greatly stimulated by calcium. The increase in this activity to high levels that occurs at confluence could be almost completely suppressed by retinoic acid in the medium. The soluble form (type II) in the SCC-12B2 cells was induced in growing or confluent cultures by retinoic acid independent of the calcium concentration in the medium, but the 50% effective concentration (100 nM) for its stimulation was approximately 50-fold higher than the 50% effective concentration for suppression of the type I enzyme (2 nM). Thus, these enzymes appear to be distinct and independently regulated. This conclusion is supported by the finding that SCC-4 and SCC-9 almost exclusively expressed types II and I forms, respectively. In contrast to the results with neoplastic cells, in cultured normal epidermal cells type I enzyme comprised the overwhelming majority of activity and was only partially (75-90%) suppressible by retinoic acid, while type II enzyme seemed poorly if at all stimulable.

Thus, the SCC lines appear appropriate for studying biochemical mechanisms of action of certain physiological agents, the molecular basis for altered regulation of differentiated function in neoplastic cells, and the origin of diversity within tumors.


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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 - Calcium, 2 grams per day, orally);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);


- 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;

- Pleural Mesothelioma: clinical records on 11 patients treated with Di Bella's Method;

- Malignant pleural mesothelioma, stage T3-T4. Consideration of a case study;

- Excellent result in a Mesothelioma case treated exclusively with Di Bella Method for over 4 years and still treatment with positive results;

- Neuroblastoma: Complete objective response to biological treatment;

- Oesophageal squamocellular carcinoma: a complete and objective response;

- 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.