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The use of variations in proteomes to predict, prevent, and personalize treatment for clinically nonfunctional pituitary adenomas.

Zhan X, Desiderio DM - EPMA J (2010)

Bottom Line: Unlike functional pituitary adenomas, nonfunctional (NF) pituitary adenomas account for ∼30% of pituitary tumors, and are large enough to cause blindness; because they do not cause any clinical hormone hypersecretion, they are difficult to detect at an early stage; and hypopituitarism results.No effective molecular biomarkers or chemical therapy have been approved for the clinical setting.Changes in protein expression and protein modifications, individually or in combination, might be biomarkers to predict the disease, monitor the tumor progression, and develop an accurate molecular classification for personalized patient treatment.

View Article: PubMed Central - PubMed

Affiliation: Charles B. Stout Neuroscience Mass Spectrometry Laboratory, The University of Tennessee Health Science Center, 847 Monroe Avenue, Room 117, Memphis, TN 38163 USA.

ABSTRACT
Pituitary adenomas account for ∼10% of intracranial tumors, and they cause the compression of nearby structures and the inappropriate expression of pituitary hormones. Unlike functional pituitary adenomas, nonfunctional (NF) pituitary adenomas account for ∼30% of pituitary tumors, and are large enough to cause blindness; because they do not cause any clinical hormone hypersecretion, they are difficult to detect at an early stage; and hypopituitarism results. No effective molecular biomarkers or chemical therapy have been approved for the clinical setting. Because an NF pituitary adenoma is highly heterogeneous, differences in the proteins (the proteome) can distinguish among those heterogeneity structures. The components of a proteome dynamically change as an NF adenoma progresses. Changes in protein expression and protein modifications, individually or in combination, might be biomarkers to predict the disease, monitor the tumor progression, and develop an accurate molecular classification for personalized patient treatment. The modalities of proteomic variation might also be useful in the interventional prevention and personalized treatment of patients to halt the occurrence and progression of NF pituitary adenomas.

No MeSH data available.


Related in: MedlinePlus

Pathway component for cell cycle G2/M DNA damage checkpoint regulation. The various shapes of nodes denote the different functions. A duplicated shape means this node contains multiple components. An arrow denotes the pathway direction. A line with a small circle denotes a biological result. Reproduced from Zhan and Desiderio [22], with permission from BioMed Central open access journal; copyright remains with the authors
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Fig9: Pathway component for cell cycle G2/M DNA damage checkpoint regulation. The various shapes of nodes denote the different functions. A duplicated shape means this node contains multiple components. An arrow denotes the pathway direction. A line with a small circle denotes a biological result. Reproduced from Zhan and Desiderio [22], with permission from BioMed Central open access journal; copyright remains with the authors

Mentions: Four pathway-network systems, including mitochondrial dysfunction, oxidative stress, cell-cycle dysregulation, and MAPK-signal abnormality for the NF adenoma, were generated from those DEP and nitroprotein data [22]. Those four pathway-network systems have been described in detail [22]. (i) Mitochondrial dysfunctions underlie a broad spectrum of human diseases [39, 40] that includes cancer [41, 42], neurodegenerative diseases [43], cardiovascular diseases [44], diabetes mellitus [45], and inflammatory diseases [46, 47]. Notable differences in the structure and function of mitochondria appear between cancer and normal cells [41, 42]. Mitochondrial dysfunctions have been proposed as a cause of cancer [48], are a biomarker for the early detection of cancer, and are a therapeutic target for cancer. Figure 7 shows the canonical pathway of mitochondrial dysfunctions [22]. Mitochondrial dysfunction could be confirmed with a mitochondrial morphological change and the increased number of mitochondria in a human pituitary tumor [49–52]. Mitochondria are emerging as biomarker targets for the early detection of, and for novel therapeutic targets in, cancer [48, 53–56]. (ii) Oxidative stress occurs when the balance is disturbed between an upload of free-radical/reactive oxygen/nitrogen species (ROS/RNS) from in vivo formation and from in vitro environmental carcinogens, and the capability of endogenous antioxidant defense mechanisms to remove those reactive species [57, 58]. Many studies have indicated that ROS and RNS are involved in pituitary adenoma pathology [59–61]. A nitroproteomics study [31] discovered nine tyrosine-nitrated proteins in human pituitary adenoma tissues, and each tyrosine nitration site is located within an important protein domain to alter protein functions. However, with the formation of ROS and RNS, the in vivo antioxidative mechanism is also initiated against ROS/RNS [62]. Pivotal to the antioxidant response is the transcription factor Nrf2 (nuclear factor-E2-related factor-2). DEP and nitroproteomic data clearly reveal that the Nrf2-mediated oxidative-stress response pathway system (Fig. 8) is involved in an NF pituitary adenoma. Any decrease in the capability of this antioxidant protective system could increase the susceptibility to oxidative stress, tumor inflammation, carcinogen toxicity, and tumorigenesis. Therefore, the oxidative stress-antioxidative stress-response system could be the novel target to develop effective therapeutic agents that could be used for human pituitary adenomas [63, 64]. (iii) Cell-cycle dysregulation is involved in an NF pituitary adenoma. The basic biological characteristics of tumor cells are the unrestricted proliferation and growth that are controlled by the dysregulated cell-cycle. The cell cycle is regulated by a cyclically operating biochemical system that includes cyclins, cyclin-dependent kinases (CDK), and their inhibitors (CDKI) [65]. Studies have demonstrated that the ectopic expression of cyclin D and the overexpresion of Cyclins A, B, and E occur in an NF pituitary adenoma to regulate different phases of the cell cycle, and to accelerate the progression of the cell-cycle [65]. The details on cell-cycle dysregulation in a human pituitary adenoma have been reviewed [66–69]. The pathway analysis of NF pituitary adenoma nitroproteomic data and DEP data clearly revealed the cell-cycle G2/M DNA damage checkpoint-regulation pathway (Fig. 9) in NF adenomas. The important cell-cycle regulator 14-3-3 protein was down-regulated (44-fold) in NF adenomas compared to controls (Table 2). Moreover, nitroproteomic data demonstrate that a nitrated proteasome could interfere with the functions of the ubiquitin-proteasome system in the regulation of the cell cycle. The proteasome inhibitors can induce apoptosis in GH-and prolactin-secreting rat pituitary tumor cells through a blocking of the cell cycle at the G2/M transition [70]. (iv) MAPK-signaling abnormality operates in an NF pituitary adenoma. MAPK-signaling pathways link the extracelluar signal stimuli to functional cellular processes such as growth, proliferation, migration, and apoptosis. The basic MAPK pathway is stimulus (mitogens, growth factors, cytokines, stress, etc.) ➔ G-protein (Ras, Rac, Cdc42, Rho) ➔ MAPKKK (Raf, Tpl2, MEKK, MLK, TAK, ASK, TAO) ➔ MAPKK (MEK) ➔ MAPK (ERK, JNK, P38) to generate responses (proliferation, differentiation, apoptosis, and migration). ERKs (extracellular signal-regulated kinases), JNKs (c-Jun N-terminal kinases), and p38-MAPKs are the three main subfamilies of MAPKs. The details of MAPK-signaling pathways in cancer have been reviewed [71–73]. The MAPK pathways are emerging as potential therapeutic targets for cancer [74, 75], and the development of inhibitors of MAPK pathways has a growing importance in cancer therapy. The pathway analyses of NF adenoma proteomic data clearly demonstrate that MAPK-signaling pathways are involved in pituitary tumorigenesis. DEP proteomic data show that Ras, ERK, JNK, p38-MAPK, Akt, TNF, TGFb1, MAPK, and NFkB are the key nodes in their pathway networks, and that ERK/MAPK signaling (Fig. 10) is the significant canonical pathway in adenomas. The nitroproteomic data of NF adenomas show that TNF and IL1B are the key nodes in their pathway networks, and that p38-MAPK signaling (Fig. 11) is the significant canonical pathway that participates in an oxidative-stress response in an adenoma. Moreover, the PKA type I beta regulatory subunit is nitrated in human pituitary adenomas (Fig. 6; Table 3), and tyrosine nitration occurs within the dimerization region [31]; those nitrations could interfere with dimerization and affect PKA activity to suppress Raf activity. Recent studies demonstrate that an overexpression of B-Raf mRNA and protein is a feature of NF adenomas; that overactivity highlights an overactivity of the Ras-B-Raf-MAP kinase pathway to promote pituitary tumorigenesis [76], and that the low levels of Raf kinase inhibitory protein (RKIP) in a GH-pituitary adenoma correlate with a poor clinical response to somatostatin analog therapy because RKIP can bind to and inhibit Raf1 kinase to attenuate MAPK signaling [77].Fig. 7


The use of variations in proteomes to predict, prevent, and personalize treatment for clinically nonfunctional pituitary adenomas.

Zhan X, Desiderio DM - EPMA J (2010)

Pathway component for cell cycle G2/M DNA damage checkpoint regulation. The various shapes of nodes denote the different functions. A duplicated shape means this node contains multiple components. An arrow denotes the pathway direction. A line with a small circle denotes a biological result. Reproduced from Zhan and Desiderio [22], with permission from BioMed Central open access journal; copyright remains with the authors
© Copyright Policy
Related In: Results  -  Collection

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Fig9: Pathway component for cell cycle G2/M DNA damage checkpoint regulation. The various shapes of nodes denote the different functions. A duplicated shape means this node contains multiple components. An arrow denotes the pathway direction. A line with a small circle denotes a biological result. Reproduced from Zhan and Desiderio [22], with permission from BioMed Central open access journal; copyright remains with the authors
Mentions: Four pathway-network systems, including mitochondrial dysfunction, oxidative stress, cell-cycle dysregulation, and MAPK-signal abnormality for the NF adenoma, were generated from those DEP and nitroprotein data [22]. Those four pathway-network systems have been described in detail [22]. (i) Mitochondrial dysfunctions underlie a broad spectrum of human diseases [39, 40] that includes cancer [41, 42], neurodegenerative diseases [43], cardiovascular diseases [44], diabetes mellitus [45], and inflammatory diseases [46, 47]. Notable differences in the structure and function of mitochondria appear between cancer and normal cells [41, 42]. Mitochondrial dysfunctions have been proposed as a cause of cancer [48], are a biomarker for the early detection of cancer, and are a therapeutic target for cancer. Figure 7 shows the canonical pathway of mitochondrial dysfunctions [22]. Mitochondrial dysfunction could be confirmed with a mitochondrial morphological change and the increased number of mitochondria in a human pituitary tumor [49–52]. Mitochondria are emerging as biomarker targets for the early detection of, and for novel therapeutic targets in, cancer [48, 53–56]. (ii) Oxidative stress occurs when the balance is disturbed between an upload of free-radical/reactive oxygen/nitrogen species (ROS/RNS) from in vivo formation and from in vitro environmental carcinogens, and the capability of endogenous antioxidant defense mechanisms to remove those reactive species [57, 58]. Many studies have indicated that ROS and RNS are involved in pituitary adenoma pathology [59–61]. A nitroproteomics study [31] discovered nine tyrosine-nitrated proteins in human pituitary adenoma tissues, and each tyrosine nitration site is located within an important protein domain to alter protein functions. However, with the formation of ROS and RNS, the in vivo antioxidative mechanism is also initiated against ROS/RNS [62]. Pivotal to the antioxidant response is the transcription factor Nrf2 (nuclear factor-E2-related factor-2). DEP and nitroproteomic data clearly reveal that the Nrf2-mediated oxidative-stress response pathway system (Fig. 8) is involved in an NF pituitary adenoma. Any decrease in the capability of this antioxidant protective system could increase the susceptibility to oxidative stress, tumor inflammation, carcinogen toxicity, and tumorigenesis. Therefore, the oxidative stress-antioxidative stress-response system could be the novel target to develop effective therapeutic agents that could be used for human pituitary adenomas [63, 64]. (iii) Cell-cycle dysregulation is involved in an NF pituitary adenoma. The basic biological characteristics of tumor cells are the unrestricted proliferation and growth that are controlled by the dysregulated cell-cycle. The cell cycle is regulated by a cyclically operating biochemical system that includes cyclins, cyclin-dependent kinases (CDK), and their inhibitors (CDKI) [65]. Studies have demonstrated that the ectopic expression of cyclin D and the overexpresion of Cyclins A, B, and E occur in an NF pituitary adenoma to regulate different phases of the cell cycle, and to accelerate the progression of the cell-cycle [65]. The details on cell-cycle dysregulation in a human pituitary adenoma have been reviewed [66–69]. The pathway analysis of NF pituitary adenoma nitroproteomic data and DEP data clearly revealed the cell-cycle G2/M DNA damage checkpoint-regulation pathway (Fig. 9) in NF adenomas. The important cell-cycle regulator 14-3-3 protein was down-regulated (44-fold) in NF adenomas compared to controls (Table 2). Moreover, nitroproteomic data demonstrate that a nitrated proteasome could interfere with the functions of the ubiquitin-proteasome system in the regulation of the cell cycle. The proteasome inhibitors can induce apoptosis in GH-and prolactin-secreting rat pituitary tumor cells through a blocking of the cell cycle at the G2/M transition [70]. (iv) MAPK-signaling abnormality operates in an NF pituitary adenoma. MAPK-signaling pathways link the extracelluar signal stimuli to functional cellular processes such as growth, proliferation, migration, and apoptosis. The basic MAPK pathway is stimulus (mitogens, growth factors, cytokines, stress, etc.) ➔ G-protein (Ras, Rac, Cdc42, Rho) ➔ MAPKKK (Raf, Tpl2, MEKK, MLK, TAK, ASK, TAO) ➔ MAPKK (MEK) ➔ MAPK (ERK, JNK, P38) to generate responses (proliferation, differentiation, apoptosis, and migration). ERKs (extracellular signal-regulated kinases), JNKs (c-Jun N-terminal kinases), and p38-MAPKs are the three main subfamilies of MAPKs. The details of MAPK-signaling pathways in cancer have been reviewed [71–73]. The MAPK pathways are emerging as potential therapeutic targets for cancer [74, 75], and the development of inhibitors of MAPK pathways has a growing importance in cancer therapy. The pathway analyses of NF adenoma proteomic data clearly demonstrate that MAPK-signaling pathways are involved in pituitary tumorigenesis. DEP proteomic data show that Ras, ERK, JNK, p38-MAPK, Akt, TNF, TGFb1, MAPK, and NFkB are the key nodes in their pathway networks, and that ERK/MAPK signaling (Fig. 10) is the significant canonical pathway in adenomas. The nitroproteomic data of NF adenomas show that TNF and IL1B are the key nodes in their pathway networks, and that p38-MAPK signaling (Fig. 11) is the significant canonical pathway that participates in an oxidative-stress response in an adenoma. Moreover, the PKA type I beta regulatory subunit is nitrated in human pituitary adenomas (Fig. 6; Table 3), and tyrosine nitration occurs within the dimerization region [31]; those nitrations could interfere with dimerization and affect PKA activity to suppress Raf activity. Recent studies demonstrate that an overexpression of B-Raf mRNA and protein is a feature of NF adenomas; that overactivity highlights an overactivity of the Ras-B-Raf-MAP kinase pathway to promote pituitary tumorigenesis [76], and that the low levels of Raf kinase inhibitory protein (RKIP) in a GH-pituitary adenoma correlate with a poor clinical response to somatostatin analog therapy because RKIP can bind to and inhibit Raf1 kinase to attenuate MAPK signaling [77].Fig. 7

Bottom Line: Unlike functional pituitary adenomas, nonfunctional (NF) pituitary adenomas account for ∼30% of pituitary tumors, and are large enough to cause blindness; because they do not cause any clinical hormone hypersecretion, they are difficult to detect at an early stage; and hypopituitarism results.No effective molecular biomarkers or chemical therapy have been approved for the clinical setting.Changes in protein expression and protein modifications, individually or in combination, might be biomarkers to predict the disease, monitor the tumor progression, and develop an accurate molecular classification for personalized patient treatment.

View Article: PubMed Central - PubMed

Affiliation: Charles B. Stout Neuroscience Mass Spectrometry Laboratory, The University of Tennessee Health Science Center, 847 Monroe Avenue, Room 117, Memphis, TN 38163 USA.

ABSTRACT
Pituitary adenomas account for ∼10% of intracranial tumors, and they cause the compression of nearby structures and the inappropriate expression of pituitary hormones. Unlike functional pituitary adenomas, nonfunctional (NF) pituitary adenomas account for ∼30% of pituitary tumors, and are large enough to cause blindness; because they do not cause any clinical hormone hypersecretion, they are difficult to detect at an early stage; and hypopituitarism results. No effective molecular biomarkers or chemical therapy have been approved for the clinical setting. Because an NF pituitary adenoma is highly heterogeneous, differences in the proteins (the proteome) can distinguish among those heterogeneity structures. The components of a proteome dynamically change as an NF adenoma progresses. Changes in protein expression and protein modifications, individually or in combination, might be biomarkers to predict the disease, monitor the tumor progression, and develop an accurate molecular classification for personalized patient treatment. The modalities of proteomic variation might also be useful in the interventional prevention and personalized treatment of patients to halt the occurrence and progression of NF pituitary adenomas.

No MeSH data available.


Related in: MedlinePlus