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Expression of apoptosis regulators in cutaneous malignant melanoma
1Department of Pathology, University of British Columbia, Vancouver Hospital, Canada.
Abstract:
Metastatic malignant melanoma (MM) is usually incurable and responds poorly to chemotherapy. Because many cytotoxic drugs cause cell death by inducing apoptosis, an imbalance of apoptosis regulatory proteins may contribute to MM treatment resistance. We have previously shown reduced expression of Bcl-2 protein, a negative regulator of apoptosis, in MM as compared with benign nevi. It is hypothesized that other apoptosis regulators may be involved in survival of MM cells. We examined the expression of Bax, Bcl-2, Bcl-X, and Mcl-1 in human benign nevi, primary MM, and metastatic MM using immunohistochemistry. Results were confirmed with Western blotting. The proapoptotic protein, Bax, was surprisingly overexpressed in all MM samples compared with benign nevi. Interestingly, in most MM samples there was overexpression of Mcl-1 or Bcl-XL, both negative regulators of apoptosis. Increased expression of Mcl-1 and Bcl-XL was first observed in thin primary melanomas, suggesting that up-regulation of these proteins represents a relatively early event associated with malignant transformation in MM. As published previously, the majority of primary and metastatic MM exhibited reduced Bcl-2 levels. We conclude that the apoptosis inhibitors Bcl-XL or Mcl-1, alone or in combination, may circumvent the normal cell death pathway, contributing to the pathogenesis and treatment resistance in metastatic MM.
Insights
Metastatic melanoma cells resist treatment partly due to altered apoptosis regulators. Overexpression of Bcl-XL or Mcl-1, inhibitors of programmed cell death, may drive melanoma survival and treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Metastatic malignant melanoma (MM) is often incurable and chemotherapy-resistant.
- Chemotherapy resistance in MM may stem from dysregulation of apoptosis (programmed cell death).
- Previous studies indicated reduced Bcl-2 protein expression in MM, a key apoptosis inhibitor.
Purpose of the Study:
- To investigate the expression of other apoptosis regulators (Bax, Bcl-XL, Mcl-1) in benign nevi, primary MM, and metastatic MM.
- To determine the role of these regulators in the pathogenesis and treatment resistance of MM.
Main Methods:
- Immunohistochemistry was used to examine protein expression in human tissue samples.
- Western blotting confirmed the immunohistochemistry results.
- Expression levels of Bax, Bcl-2, Bcl-XL, and Mcl-1 were analyzed.
Main Results:
- Bax, a pro-apoptotic protein, was surprisingly overexpressed in all MM samples compared to benign nevi.
- Mcl-1 and Bcl-XL, apoptosis inhibitors, were overexpressed in most MM samples.
- Upregulation of Mcl-1 and Bcl-XL was observed early in thin primary melanomas, suggesting an early role in malignant transformation.
- Reduced Bcl-2 levels were confirmed in most primary and metastatic MM samples.
Conclusions:
- Overexpression of apoptosis inhibitors Bcl-XL or Mcl-1 may contribute to the pathogenesis of MM.
- These proteins, alone or combined, might circumvent normal cell death pathways, leading to treatment resistance in metastatic MM.