Phorbol ester phorbol-12-myristate-13-acetate promotes anchorage-independent growth and survival of melanomas through MEK-independent activation of ERK1/2
- Department of Pathology, Norwegian Radium Hospital, HF, 0310 Oslo (Norway)
- Department of Pathology, The Norwegian Radium Hospital, HF, 0310 Oslo (Norway)
- Department of Environmental and Occupational Cancer, Norwegian Radium Hospital, HF, 0310 Oslo (Norway)
The phorbol ester, phorbol-12-myristate-13-acetate (PMA), an activator of PKCs, is known to stimulate the in vitro growth of monolayer cultures of normal human melanocytes whereas it inhibits the growth of most malignant melanoma cell lines. We examined the effect of PMA on proliferation and survival of melanoma cells grown as multicellular aggregates in suspension (spheroids), and aimed to elucidate downstream targets of PKC signaling. In contrast to monolayer cultures, PMA increased cell proliferation as well as protected melanoma cells from suspension-mediated apoptosis (anoikis). Supporting the importance of PKC in anchorage-independent growth, treatment of anoikis-resistant melanoma cell lines with antisense oligonucleotides against PKC-{alpha}, or the PKC inhibitor Goe6976, strongly induced anoikis. PMA induced activation of ERK1/2, but this effect was not prevented by the MEK inhibitors PD98059 or by U0126. Whereas PD98059 treatment alone led to marked activation of the pro-apoptotic Bim and Bad proteins and significantly increased anoikis, these effects were clearly reversed by PMA. In conclusion, our results indicate that the protective effect of PMA on anchorage-independent survival of melanoma cells at least partly is mediated by MEK-independent activation of ERK1/2 and inactivation of downstream pro-apoptotic effector proteins.
- OSTI ID:
- 20630909
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 329, Issue 1; Other Information: DOI: 10.1016/j.bbrc.2005.01.143; PII: S0006-291X(05)00200-7; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Protein kinase C-{beta}, fibronectin, {alpha}{sub 5}{beta}{sub 1}-integrin and tumor necrosis factor-{alpha} are required for phorbol diester-induced apoptosis in human myeloid leukemia cells in human myeloid leukemia cells.
The effect of the PKC inhibitor calphostin C and the PKC agonist phorbol 12-myristate 13-acetate on regulation of cytosolic Ca{sup 2+} in mammalian skeletal muscle cells