Regulation of prostate-specific antigen (PSA) gene expression and release in LNCaP prostate cancer by antagonists of growth hormone-releasing hormone and vasoactive intestinal peptide

Abstract

BACKGROUND: Prostate-specific antigen (PSA) is the best tumor marker for diagnosis and prognosis of prostatic carcinoma. The secretion of PSA from LNCaP human prostate cancer cells is influenced by acute stimuli such as vasoactive intestinal peptide (VIP), growth hormone-releasing hormone (GHRH), and chronic stimuli like androgens.

METHODS: To study the regulation of basal and VIP/GHRH or androgen-stimulated secretion from LNCaP cells, we used a superfusion system, which allowed us to simultaneously measure PSA gene expression, PSA secretion, and cAMP release from the same cancer cells. LNCaP cancer cells were also implanted orthotopically into nude mice.

RESULTS: VIP (30 pM-3 nM), GHRH (3 nM-300 nM), and dihydrotestosterone (100 nM) induced a significant increase in PSA gene expression, PSA secretion, and cAMP release. The dose and time-dependent effects of peptides were manifested only in the presence of androgens. At the end of continuous stimulation of cells with 1 nM VIP for 2 hr, large amounts of stored immunoreactive PSA still remained in the cells. Adenylate cyclase activator, forskolin (FSK), significantly increased PSA secretion and gene expression, and potassium, which causes nonspecific depolarization of membranes, augmented gene expression, and secretion of PSA, but did not influence cAMP release. This suggests that PSA secretion is regulated by cAMP-dependent as well as cAMP-independent pathways. In superfusion system, stimulatory effects of VIP and GHRH on PSA secretion were inhibited by VIP antagonist JV-1-53, and less by GHRH antagonist JV-1-38. In cell cultures, JV-1-38 had a stronger inhibitory effect on proliferation, indicating an involvement of the recently discovered tumoral GHRH receptors in this process. In nude mice, with orthotopically implanted LNCaP cancer cells, GHRH antagonist JV-1-38 alone or androgen ablation by castration had no effect on tumor growth and PSA levels. However, castration combined with treatment with GHRH antagonist, significantly decreased tumor growth and PSA secretion.

CONCLUSIONS: Our findings suggest that the secretion of PSA is regulated rather than constitutive, contrary to previous reports. In addition, the effect of GHRH and VIP antagonists on PSA secretion from prostate cancer cells is not correlated with their antiproliferative action.

 

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- Official Web Site: The Di Bella Method;

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

- Publication: 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: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (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) 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;

- Oesophageal squamocellular carcinoma: a complete and objective response;

- 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;

- Neuroblastoma: Complete objective response to biological treatment;

- 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.