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Expression of apoptosis regulators in cutaneous T-cell lymphoma (CTCL) cells
Chun-Lei Zhang1, Jivko Kamarashev, Jian-Zhong Qin
1Department of Dermatology, University Hospital of Zurich, CH-8091 Zürich, Switzerland.
Abstract:
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.
Insights
Malignant cutaneous T-cell lymphoma (CTCL) cells survive due to anti-apoptotic proteins like Bcl-xL and Mcl-1. In CTCL, Bad is inactivated, and Bax is non-functional, contributing to drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin lymphoma.
- Understanding the molecular mechanisms of apoptosis in CTCL is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the expression and function of Bcl-2 gene family members in CTCL cell lines and patient lesions.
- To determine the role of these proteins in CTCL cell survival and drug resistance.
Main Methods:
- Analysis of Bcl-2 gene family member expression in CTCL cell lines and skin lesions using molecular techniques.
- Assessment of protein inactivation through phosphorylation and subcellular localization.
- Evaluation of drug-induced apoptosis in CTCL cell lines.
Main Results:
- Bcl-xL and Mcl-1 (anti-apoptotic) and Bad and Bax (pro-apoptotic) proteins were expressed in CTCL.
- Bad was inactivated by phosphorylation, and Bax was non-functional, hindering apoptosis.
- Mcl-1 expression increased in later-stage CTCL lesions.
- CTCL cells showed resistance to chlorambucil and sulindac.
Conclusions:
- Overexpression of Bcl-xL and Mcl-1, coupled with inactivated Bad and non-functional Bax, promotes CTCL cell survival.
- These factors contribute to the resistance of CTCL to conventional anti-cancer drugs.