Expression of apoptosis regulators in cutaneous T-cell lymphoma (CTCL) cells.
This study examined cutaneous T-cell lymphoma (CTCL) cell lines and cutaneous lesions for the presence of Bcl-2 gene family members and found that the two apoptosis-inhibiting members Bcl-xL and Mcl-1 and the two apoptosis-supporting members Bad and Bax were expressed. However, Bad was at least partially inactivated by phosphorylation. In skin lesions, the translocation of Bad from the nucleus to the cytoplasm may reflect the Bad inactivation by phosphorylation identified in vivo. Bax is also ineffective, as the non-steroidal anti-inflammatory drug sulindac, whose cytotoxic effect is mediated by Bax, could not induce apoptosis in CTCL cell lines. The expression of Bcl-2, Bcl-xL, and Mcl-1 may therefore be sufficient to guarantee the survival of malignant CTCL cells. The Bcl-x, Mcl-1, Bad, and Bax proteins were also expressed in all CTCL skin lesions tested. In two patients from whom two biopsies from two different time points of the disease were available, a significant increase in Mcl-1 expression was found in the later-stage skin lesion. Overexpression of Mcl-1 and synthesis of non-functional Bax may be responsible for the resistance of CTCL cells to the anti-cancer drugs chlorambucil and sulindac.
Zhang
Chun-Lei
CL
Department of Dermatology, University Hospital of Zurich, CH-8091 Zürich, Switzerland.
Kamarashev
Jivko
J
Qin
Jian-Zhong
JZ
Burg
Günter
G
Dummer
Reinhard
R
Döbbeling
Udo
U
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D015870:Gene Expression; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D013467:Sulindac / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494819:BAD protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D013467:Sulindac