Resistance to transforming growth factor β-mediated tumor suppression in melanoma: are multiple mechanisms in place?
Resistance to transforming growth factor (TGF) β-mediated tumor suppression in melanoma appears to be a crucial step in tumor aggressiveness since it is usually coupled with the ability of TGFβ to drive the oncogenic process via autocrine and paracrine effects. In this review, we will focus mainly on the mechanisms of escape from TGFβ-induced cell cycle arrest because the mechanisms of resistance to TGFβ-mediated apoptosis are still essentially speculative. As expected, some of these mechanisms can directly affect the function of the main downstream effectors of TGFβ, Smad2 and Smad3, resulting in compromised Smad-mediated antiproliferative activity. Other mechanisms can counteract or overcome TGFβ-mediated cell cycle arrest independently of the Smads. In melanoma, some models of resistance to TGFβ have been suggested and will be described. In addition, we propose additional models of resistance taking into consideration the information available on the dysregulation of fundamental cellular effectors and signaling pathways in melanoma.
Lasfar
Ahmed
A
Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, University Hospital Cancer Center, 205 South Orange Avenue, Newark, NJ 07103, USA.
Cohen-Solal
Karine A
KA
D017209:Apoptosis; D002453:Cell Cycle; D003285:Contractile Proteins / Q000502:physiology; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D018450:Disease Progression; D064448:Filamins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D016259:Genes, myc; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008545:Melanoma / Q000473:pathology* / Q000517:prevention & control; D008840:Microfilament Proteins / Q000502:physiology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000502:physiology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology; D015398:Signal Transduction; D051899:Smad2 Protein / Q000502:physiology; D051900:Smad3 Protein / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
C493956:CDKN1A protein, human; D003285:Contractile Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C085126:FOXO1 protein, human; D064448:Filamins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4