Expression of Activated Akt and PTEN in Malignant Melanomas
Expression of Activated Akt and PTEN in Malignant Melanomas
Our purpose was to analyze, by immunohistochemistry, the expression of activated serine-threonine protein kinase B (p-Akt) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in benign nevi and primary and metastatic melanomas and to correlate the expression level with clinical variables. We observed cytoplasmic and/or nuclear expression of p-Akt in 22 (54%) of 41 benign nevi, 112 (71.3%) of 157 primary tumors, and 50 (71%) of 70 metastases. Cytoplasmic PTEN staining was observed in 0 (0%), 152 (87.7%), and 64 (90%) of 41 nevi, 162 primary tumors, and 71 metastases, respectively. A significant positive correlation was seen between PTEN and p-Akt cytoplasmic expression (P < .001) in primary melanomas. Cytoplasmic p-Akt expression showed a positive association with cyclin A in superficial spreading (P = .038) but not in nodular (P = .22) melanomas. Cytoplasmic p-Akt and PTEN expression did not have an impact on disease-free and overall survival, but complete lack of nuclear p-Akt expression was a predictor of shorter disease-free survival (P = .025) for patients with superficial spreading melanoma.
The coordinated balance between cell division, growth, and programmed cell death (apoptosis) maintains cellular homeostasis, and disturbance of this balance might result in cancer development. The phosphoinositide 3-kinase (PI3K) signaling pathway has been demonstrated to have an important role in the regulation of the aforementioned processes, and dysregulation of this pathway is a common feature of many cancers, including melanoma (reviewed by Vivanco and Sawyers).
Activated PI3K catalyzes the production of phosphatidyl-inositol-3 4,5-triphosphate (PIP3) at the cell membrane, which in turn leads to recruitment, phosphorylation, and activation of the serine-threonine protein kinase B (Akt). Activated Akt (p-Akt) has multiple effects on cell cycle regulation through phosphorylation and inactivation of 2 major cell cycle regulators, p27 and p21, as well as through prevention of cyclin D1 degradation by inactivation of glycogen synthase kinase 3β. p-Akt also suppresses apoptosis by phosphorylation and inactivation of proapoptotic proteins such as Bad, caspase 9, and the Forkhead family of transcription factors, which induces expression of genes crucial for apoptosis. Overexpression and activation of Akt are the most common alterations leading to hyperactivation of the PI3K signaling pathway. Amplification of the gene encoding Akt has been found in ovarian, cervical, breast, prostate, and pancreatic cancers. Moreover, a number of studies have demonstrated activation of Akt in cells harboring inactivation of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor gene due to deletions and mutations.
The PTEN protein is a phosphatase with activity toward acidic protein and lipid substrates. Its primary function is dephosphorylation of PIP3, leading to negative regulation of the PI3K/Akt pathway. Furthermore, PTEN has been shown to influence cell adhesion, migration, and invasion by dephosphorylation of focal adhesion kinase, leading to inhibition of focal adhesion formation. In addition, PTEN inhibits phosphorylation of the adaptor protein Shc and suppresses the mitogen-activated protein kinase (MAPK) signaling pathway. Germline mutations of PTEN have been observed in autosomal dominant cancer syndromes: Cowden disease and Bannayan-Zonana syndrome. Loss of PTEN expression due to loss of heterozygosity and mutations has been observed in a variety of human malignant neoplasms, including breast, thyroid, endometrial, and prostate cancers and glioblastomas. Furthermore, PTEN mutations or loss of expression have been detected in 30% to 50% of melanoma cell lines and in 5% to 20% of uncultured melanomas. However, it is unclear whether abrogation in PTEN is an early or late event and what role it has in melanoma progression.
The aims of the present study were to address the association between activation of the PI3K/Akt signaling pathway and progression of malignant melanomas and to study the relationship between p-Akt and PTEN expression, cell cycle markers, and known prognostic factors. To gain more insight into the complex signaling in melanomas, we also evaluated the association between activation of the PI3K/Akt and MAPK pathways.
Our purpose was to analyze, by immunohistochemistry, the expression of activated serine-threonine protein kinase B (p-Akt) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in benign nevi and primary and metastatic melanomas and to correlate the expression level with clinical variables. We observed cytoplasmic and/or nuclear expression of p-Akt in 22 (54%) of 41 benign nevi, 112 (71.3%) of 157 primary tumors, and 50 (71%) of 70 metastases. Cytoplasmic PTEN staining was observed in 0 (0%), 152 (87.7%), and 64 (90%) of 41 nevi, 162 primary tumors, and 71 metastases, respectively. A significant positive correlation was seen between PTEN and p-Akt cytoplasmic expression (P < .001) in primary melanomas. Cytoplasmic p-Akt expression showed a positive association with cyclin A in superficial spreading (P = .038) but not in nodular (P = .22) melanomas. Cytoplasmic p-Akt and PTEN expression did not have an impact on disease-free and overall survival, but complete lack of nuclear p-Akt expression was a predictor of shorter disease-free survival (P = .025) for patients with superficial spreading melanoma.
The coordinated balance between cell division, growth, and programmed cell death (apoptosis) maintains cellular homeostasis, and disturbance of this balance might result in cancer development. The phosphoinositide 3-kinase (PI3K) signaling pathway has been demonstrated to have an important role in the regulation of the aforementioned processes, and dysregulation of this pathway is a common feature of many cancers, including melanoma (reviewed by Vivanco and Sawyers).
Activated PI3K catalyzes the production of phosphatidyl-inositol-3 4,5-triphosphate (PIP3) at the cell membrane, which in turn leads to recruitment, phosphorylation, and activation of the serine-threonine protein kinase B (Akt). Activated Akt (p-Akt) has multiple effects on cell cycle regulation through phosphorylation and inactivation of 2 major cell cycle regulators, p27 and p21, as well as through prevention of cyclin D1 degradation by inactivation of glycogen synthase kinase 3β. p-Akt also suppresses apoptosis by phosphorylation and inactivation of proapoptotic proteins such as Bad, caspase 9, and the Forkhead family of transcription factors, which induces expression of genes crucial for apoptosis. Overexpression and activation of Akt are the most common alterations leading to hyperactivation of the PI3K signaling pathway. Amplification of the gene encoding Akt has been found in ovarian, cervical, breast, prostate, and pancreatic cancers. Moreover, a number of studies have demonstrated activation of Akt in cells harboring inactivation of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor gene due to deletions and mutations.
The PTEN protein is a phosphatase with activity toward acidic protein and lipid substrates. Its primary function is dephosphorylation of PIP3, leading to negative regulation of the PI3K/Akt pathway. Furthermore, PTEN has been shown to influence cell adhesion, migration, and invasion by dephosphorylation of focal adhesion kinase, leading to inhibition of focal adhesion formation. In addition, PTEN inhibits phosphorylation of the adaptor protein Shc and suppresses the mitogen-activated protein kinase (MAPK) signaling pathway. Germline mutations of PTEN have been observed in autosomal dominant cancer syndromes: Cowden disease and Bannayan-Zonana syndrome. Loss of PTEN expression due to loss of heterozygosity and mutations has been observed in a variety of human malignant neoplasms, including breast, thyroid, endometrial, and prostate cancers and glioblastomas. Furthermore, PTEN mutations or loss of expression have been detected in 30% to 50% of melanoma cell lines and in 5% to 20% of uncultured melanomas. However, it is unclear whether abrogation in PTEN is an early or late event and what role it has in melanoma progression.
The aims of the present study were to address the association between activation of the PI3K/Akt signaling pathway and progression of malignant melanomas and to study the relationship between p-Akt and PTEN expression, cell cycle markers, and known prognostic factors. To gain more insight into the complex signaling in melanomas, we also evaluated the association between activation of the PI3K/Akt and MAPK pathways.
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