We reported that biliverdin is required for formation of eyes, brain, spinal cord and other dorsal organs in amphibia. Beyond that mandatory requirement for embryogenesis, we found that biliverdin is a pleiotropic molecule capable of altering the phenotypes of a number of cancer cells to a more differentiated state. An early and common behavior caused by biliverdin is an arrest of proliferation in six cancer cells (melanoma, colon adenocarcinoma, liposarcoma, thyroid carcinoma, T and B cell lymphomas). In colon adenocarcinoma, the c Myc oncogene disapp9ears within two days of incubating with 5 x 10-7 M biliverdin. Concurrently, biliverdin slows their G1 to S transition. Subsequently, two differentiation markers, CEA and alkaline phosphatase, are up-regulated. These findings suggest that biliverdin reverses the phenotypic consequences of APC and beta catenin mutations characteristic of colon adenocarcinoma. Central to the current proposal are the documented findings that, like in colon adenocarcinoma, melanoma cells characteristically exhibit mutations in the same signaling system including GSK3beta phosphorylation sites of beta catenin and/or abnormally expressing high amounts of beta catenin itself. These mutations and over-expression lead to an increase in stable cytoplasmic beta catenin and enhanced transcription of beta catenin/Tef/Lef oncogenes, such as c Myc. The common alterations in beta catenin signaling found in colon cancer and melanoma cells calls for examination of the possibility that the dermatological malignancy also may be responsive to the effects of biliverdin and be directed along a differentiation pathway. In favor of this premise is a) our finding that biliverdin arrests cell division if SJ NEK 24 melanoma cell and b) literature reports that 12-o-tetra decanoyl phorbol 13 acetate (TPA), a molecule that up-regulates heme oxygenase 1 (HO 1) in cancer cells and, therefore, must lead to an increase in biliverdin content of these cells, also inhibits proliferation of melanoma cells. Consequently, we propose to examine the effect of biliverdin on SK MEL 24 phenotype focusing on oncogene molecules transcriptionally regulated by the beta catenin signaling system (Aim 1) and on beta catenin itself and GSK3beta, the enzyme responsible for its phosphorylation and degradation (Aim 2). These two aims will be examined by incubating the SK MEL 24 cells with biliverdin. If the results are positive, we will examined these same molecules in SK MEL 24 cells induced to synthesize biliverdin in response to phenylarsine oxide, a known activator of heme oxygenase 1 (Aim 3). Positive results will demonstrate that melanoma cells can be made to undergo differentiation and open the door to possible novel therapeutic interventions.
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