Notch signalling in primary cutaneous CD30+ lymphoproliferative disorders: a new therapeutic approach?
BACKGROUND
The oncogenic potential of deregulated Notch signalling has been described in several haematopoietic malignancies. We have previously reported an increased expression of Notch1 in primary cutaneous CD30+ lymphoproliferative disorders, lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma (pcALCL).


OBJECTIVE
To investigate the functional importance of Notch signalling in cell lines derived from pcALCL.


METHODS
Cell lines derived from pcALCL (Mac1, Mac2a and JK) were treated with different γ-secretase inhibitors (GSIs) (GSI I, IX, XX and XXI). The effects of GSIs on cell viability, apoptosis and cell cycle progression were measured as well as the impact of GSI I on the known prosurvival pathway Akt-mTOR-FOXO3a.


RESULTS
Notch family members were expressed in all investigated pcALCL cell lines. GSI I had a marked proapoptotic effect, but GSI IX, XX and XXI were much less potent. The GSI I-triggered apoptosis was preceded by an accumulation of cells in the G2/M, cyclin B1-controlled phase of the cell cycle accompanied by an increase in the cyclin-dependent kinase inhibitor, p21(WAF/Cip) . GSI I induced the nuclear translocation of proapoptotic FOXO3a, probably via an Akt-independent pathway.


CONCLUSIONS
Notch signalling may be a future therapeutic target for the treatment of advanced pcALCL.
Kamstrup
M R
MR
Department of Dermatology, Bispebjerg Hospital, Bispebjerg bakke 23, Copenhagen 2400, Denmark.
Biskup
E
E
Gniadecki
R
R
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D017730:Ki-1 Antigen / Q000032:analysis; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017730:Ki-1 Antigen; D009363:Neoplasm Proteins; D009842:Oligopeptides; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D053829:Amyloid Precursor Protein Secretases