Betulinic acid inhibits the expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in human endometrial adenocarcinoma cells.
Although betulinic acid (BA) is known to induce apoptosis and antiangiogenic response in tumor cells, the underlying mechanism of its action is unknown. Deregulation of tissue collagen metabolism is one of the consequences of neoplastic transformation. The final step of collagen degradation is mediated by prolidase [E.C.3.4.13.9] which may play a role in angiogenesis. The formation of new blood vessels is regulated by the hypoxia-inducible factor 1 (HIF-1). The expression of HIF-1 correlates with hypoxia-induced angiogenesis as a result of the induction of vascular endothelial cell growth factor (VEGF). Since BA evokes anticancer activity, its effect on collagen biosynthesis, HIF-1alpha and VEGF expressions, as well as prolidase activity and expression was studied in cultured endometrial adenocarcinoma (EA) cells. It was found that BA inhibits collagen biosynthesis in EA cells (5[(3)H] proline incorporation assay). It was accompanied by a parallel decrease in prolidase activity and expression and decrease in expressions of alpha(1) and alpha(2) integrins, HIF-1alpha, and VEGF (western immunoblot analysis) in cultured human EA cells. The data suggest that BA may have anti-angiogenic potential by inhibition of prolidase, HIF-1alpha and VEGF expressions, and inhibition of collagen biosynthesis.
Karna
Ewa
E
Department of Medicinal Chemistry, Medical University in Bialystok, Kilińskiego 1, 15-089 Bialystok, Poland.
Szoka
Lukasz
L
Palka
Jerzy A
JA
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003094:Collagen / Q000096:biosynthesis; D004150:Dipeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D039423:Integrin alpha1 / Q000378:metabolism; D039421:Integrin alpha2 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000094062:Betulinic Acid
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039423:Integrin alpha1; D039421:Integrin alpha2; D019012:Integrin beta1; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D004150:Dipeptidases; C022449:proline dipeptidase; D000094062:Betulinic Acid