Involvement of FKHRL1 in melanoma cell survival and death

Melanoma is a highly aggressive tumour characterized by a strong resistance to apoptotic stimuli that give rise to a selective advantage for tumour progression and metastasis formation. Therefore, it is of paramount importance to better understand the mechanisms involved in this resistance to apoptosis. In this report, we focused our attention on FKHRL1, a member of the forkhead family of transcription factors, which controls expression of genes involved in cell cycle progression and apoptosis. In melanoma cells, we show that IGF1, which exerts pro‐survival properties, induces the phosphorylation and nuclear exclusion of FKHRL1 in a PI3K/AKT‐dependent pathway. Moreover, we observe that over‐expression of a non‐phosphorylable mutant of FKHRL1 (FKHRL1‐TM), constitutively localized to the nucleus, promotes apoptotic cell death of melanoma cells. Finally, we find that FKHRL1‐TM decreases the expression of survivin, a member of the inhibitor of apoptosis protein and that survivin re‐expression partially rescues the deleterious effects of FKHRL1. Taken together, these findings reveal, in melanoma cells, that endogenous FKHRL1 is a downstream target of the PI3K/AKT pathway and suggest that the phosphorylation of this transcription factor may be involved in the pro‐survival effects of growth factors such as IGF1. On the other hand, forced nuclear localization of FKHRL1 decreases melanoma cell growth and may serve as a therapeutic strategy against melanoma.

[1]  K. Bille,et al.  IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin. , 2008, The Journal of investigative dermatology.

[2]  F. Holstege,et al.  FOXO3a Induces Differentiation of Bcr-Abl-transformed Cells through Transcriptional Down-regulation of Id1* , 2007, Journal of Biological Chemistry.

[3]  A. H. Yeh,et al.  Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs , 2006, Oncogene.

[4]  Fengzhi Li,et al.  Survivin study: An update of “What is the next wave?” , 2006, Journal of cellular physiology.

[5]  D. Elashoff,et al.  Survivin expression by metastatic melanoma predicts poor disease outcome in patients receiving adjuvant polyvalent vaccine , 2005, International journal of cancer.

[6]  V. A. Flørenes,et al.  Expression of activated Akt and PTEN in malignant melanomas: relationship with clinical outcome. , 2005, American journal of clinical pathology.

[7]  M. Khaled,et al.  The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis. , 2005, Genes & development.

[8]  G. Robertson.  Functional and therapeutic significance of Akt deregulation in malignant melanoma , 2005, Cancer and Metastasis Reviews.

[9]  J. Bos,et al.  FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK , 2004, The EMBO journal.

[10]  Julia M. Francis,et al.  FoxO3a and BCR-ABL Regulate cyclin D2 Transcription through a STAT5/BCL6-Dependent Mechanism , 2004, Molecular and Cellular Biology.

[11]  J. Cheng,et al.  Deregulated Akt3 Activity Promotes Development of Malignant Melanoma , 2004, Cancer Research.

[12]  M. Khaled,et al.  PI3K mediates protection against TRAIL-induced apoptosis in primary human melanocytes , 2004, Cell Death and Differentiation.

[13]  E. Borden,et al.  Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis , 2004, Cell Death and Differentiation.

[14]  Marten P Smidt,et al.  The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. , 2004, The Biochemical journal.

[15]  D. Accili,et al.  FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and Transformation , 2004, Cell.

[16]  Pamela A. Silver,et al.  A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. , 2003, Cancer cell.

[17]  A. Grimberg.  Mechanisms by which IGF-I May Promote Cancer , 2003, Cancer biology & therapy.

[18]  M. Khaled,et al.  SP-04 Microphthalmia associated transcription factor (mitf) is a target of the pi3k pathway , 2003 .

[19]  M. Khaled,et al.  Microphthalmia associated transcription factor is a target of the phosphatidylinositol-3-kinase pathway. , 2003, The Journal of investigative dermatology.

[20]  Fengzhi Li.  Survivin study: What is the next wave? , 2003, Journal of cellular physiology.

[21]  R. Medema,et al.  Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty , 2003, Journal of leukocyte biology.

[22]  G. Robertson,et al.  Loss of PTEN promotes tumor development in malignant melanoma. , 2003, Cancer research.

[23]  S. Lowe,et al.  Apoptosis and melanoma chemoresistance , 2003, Oncogene.

[24]  Rakesh Nagarajan,et al.  FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression , 2002, The Journal of Biological Chemistry.

[25]  Richard Wooster,et al.  BRAF and RAS mutations in human lung cancer and melanoma. , 2002, Cancer research.

[26]  E. Lam,et al.  Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D , 2002, Molecular and Cellular Biology.

[27]  Geert J. P. L. Kops,et al.  Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress , 2002, Nature.

[28]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[29]  S. R. Datta,et al.  DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein , 2002, Science.

[30]  E. Lam,et al.  Control of Cell Cycle Exit and Entry by Protein Kinase B-Regulated Forkhead Transcription Factors , 2002, Molecular and Cellular Biology.

[31]  C. Osborne,et al.  Forkhead Homologue in Rhabdomyosarcoma Functions as a Bifunctional Nuclear Receptor-interacting Protein with Both Coactivator and Corepressor Functions* , 2001, The Journal of Biological Chemistry.

[32]  K. Kaestner,et al.  Unified nomenclature for the winged helix/forkhead transcription factors. , 2000, Genes & development.

[33]  P. Cohen,et al.  Phosphorylation of the Transcription Factor Forkhead Family Member FKHR by Protein Kinase B* , 1999, The Journal of Biological Chemistry.

[34]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.