Physical Activity and Its Effects on Prostate Cancer
Physical Activity and Its Effects on Prostate Cancer
Although emerging data provide strong evidence of decreased prostate cancer risk following physical activity, the fundamental question still remains unanswered 'what are the signaling pathways associating physical activity and prostate cancer at the molecular and cellular level?' As discussed elsewhere in this review, the skeletal muscle produces and secretes numerous proteins. In order to elucidate the biological mechanisms associating physical activity and prostate cancer risk, it is important to identify and analyze these proteins and understand their role in the processes of normal and aberrant growth and development of the prostate gland. In addition, these proteins are altered following physical activity in healthy individuals. Understanding how physical activity alters these proteins and how they control key cellular processes might indicate their role in preventing prostate cancer. In this review, we have focused on the proteins that affect prostate growth and development and that have been shown to influence the progression of prostate cancer. Under discussion therefore, are myostatin (a myokine), follistatin, activin, inhibin and their receptors (activin receptors).
Myostatin, activin and inhibin belong to the transforming growth factor β superfamily. Myostatin is predominantly expressed in skeletal muscle cells but at low levels in cardiac muscle and adipose tissue. Its activity is controlled by transcription and posttranslational modification. It is stored as a latent complex in the extracellular space and bound to propeptide that prevents it from binding to the receptor. Other circulating proteins such as follistatin and the follistatin-like proteins also bind and inhibit myostatin. Activin is expressed in gonadal tissues where it stimulates follicle stimulating hormone (FSH) biosynthesis and secretion in the pituitary. There are three isoforms of activin: activin A (βAβA), activin B (βBβB), and activin AB (βAβB). Activin A is the major form. Its activity is regulated via its latent complex where its propeptide remains associated and prevents its binding to activin receptors or by follistatin, which binds and neutralizes its activity. Inhibin is produced in numerous organs such as the gonads, pituitary gland, placenta and corpus luteum. It downregulates FSH synthesis and inhibits FSH secretion. Two forms of inhibin exist: inhibin A (αβA) and inhibin B (αβB). The signaling of myostatin, activin and inhibin is modulated by activin receptors. The ligand (myostatin, activin or inhibin) binds to the activin receptors triggering a downstream signaling cascade that translocates Smad2/3 into the nucleus and leading to changes in gene expression. There are two types of activin receptors: type 1 and type 2. There are three subtypes of the type 1 receptor (1A, 1B and 1C) and two subtypes of the type 2 receptor (2A and 2B). Each subtype of the type 1 receptor binds to a specific type II receptor–ligand complex (Figure 3).
(Enlarge Image)
Figure 3.
A hypothetical model to explain how physical activity through different proteins is linked to prostate cancer. AR1=activin receptor type 1, AR2=activin receptor type 2, BG=betaglycan, co-SMAD=common-mediator Smad, InhBP=inhibin-binding protein, RSMAD=receptor-regulated Smads, rDNA=ribosomal DNA. (A): Under glucose-deprived conditions, follistatin expression is increased and accumulates in the nucleolus. It then binds to ribosomal DNA and represses ribosomal RNA synthesis lowering energy consumption in cancerous cells, thus promoting cancer cell survival. (B): It is not known how follistatin accumulates in the nucleolus. It may permeate the tumor cell membrane and the nuclear membrane into the nucleolus. (C): Mitochondrial-dependent apoptosis; myostatin promotes the translocation of Bax from cytosol to mitochondria resulting in metabolic stress-induced apoptosis. (D): Activin or myostatin binds to AR2, which recruits and phosphorylates AR1 activating the ligand. AR1 phosphorylates RSMAD in the presence of SARA, which binds to coSMAD and translocates to the nucleus where it binds to transcription factors causing DNA transcription. This pathway is inhibited by SMAD 6 or 7. (E): Activin or myostatin might regulate apoptosis or induce growth arrest: (i) transcriptionally by regulating apoptosis-related genes, such as XIAP, Bcl-2/Bcl-xl or Bim; (ii) through non-canonical pathways, such as JNK and Akt signaling, leading to the phosphorylation and activation of the pro-apoptotic molecules; or (iii) activin may induce dormancy of prostate cancer cells by facilitating growth arrest where cells are blocked in the G0/G1 or G2/M phases of cell cycle. (F): The binding of inhibin to the inhibin receptor (inhibin-binding protein) leads to recruitment of the AR1. This enables inhibin to inhibit growth of prostate cancer cells by complementing the antiproliferative effects of activin (inhibin has an additive inhibitory effect to that of activin). (G): Inhibin binds to AR2 preventing the recruitment of AR1. This is facilitated by betaglycan. Inhibin binds with betaglycan blocking activin access to the activin receptor. Inhibin prevents the inhibition of prostate cancer cells by antagonizing the antiproliferative effects of activin by acting in a dominant-negative mechanism with the activin receptor. (H): Follistatin can bind to activin or myostatin preventing it from binding to its receptor and antagonizing their action (apoptosis or growth arrest). For the follistatin–myostatin complex, follistatin neutralizes myostatin activity. For the follistatin–activin complex, follistatin neutralizes activin activity or mops it out of circulation by lysosomal breakdown.
Follistatin is expressed in nearly all human tissues and the highest concentrations can be found in the ovary and skin. Endothelial cells, macrophages and monocytes have also been suggested as alternative sources of follistatin. Follistatin acts as a ligand inhibitor that binds and inhibits myostatin and activin, therefore interfering with functions ascribed to both proteins. Follistatin is also part of the inhibin–activin–follistatin axis, which has an important role in the human reproductive system. There are three isoforms of follistatin—FLS315 (from pre-FLS344), FLS288 (from pre-FLS317) and FS303 (intermediate). The FLS315 variant is predominant, while the FLS288 isoform accounts for <5% of the encoded mRNA. These isoforms are widely present and differentially expressed in human tissues (Figure 3).
Myostatin inhibits muscle growth and is predominantly expressed in skeletal muscle cells. It is not known whether this protein is present in the prostate gland. However, given its role of negatively regulating muscle growth and in cancer-induced muscle wasting it may be present. The human prostate gland synthesizes follistatin, activin and inhibin. Follistatin is expressed in the basal epithelial cells and in the fibroblastic stromal, whereas activin and inhibin are predominantly localized to the epithelium. The prostate gland has been shown to express activin receptors, suggesting that these proteins have a local role in the functioning of the prostate gland. The follistatin–activin–inhibin system controls the physiological growth and functions of the prostate gland in a paracrine–autocrine manner. The proteins regulate the growth of normal prostatic epithelial cells in a paracrine manner between stromal and epithelial cells. In malignancy, epithelial tumor cell growth is regulated in an autocrine manner and may involve a different interplay between these proteins.
The mechanisms by which follistatin, myostatin, activin and inhibin facilitate proliferation, dissemination, inhibition or apoptosis of human prostate cancer cells have not been fully elucidated. However, this could be explained by (Figure 3): (1) Induction of growth arrest of prostate cancer cells thus limiting proliferation of the tumor cells at the new site. This process is facilitated by activin, which blocks the cells in the G0/G1 or G2/M phases of cell cycle. For this process to occur, activin must bind to the activin receptor. The binding of activin to its receptor can be prevented by follistatin, which antagonizes the effects of activin by binding to activin and preventing this interaction and downstream effect therefore driving proliferation and dissemination of the cells. (2) Regulation of prostate cancer cell growth or death indirectly through the regulation of energy metabolism by myostatin. Myostatin induces a metabolic change from oxidative phosphorylation to glycolysis in tumorous cells leading to mitochondrial-dependent apoptosis. Myostatin affects the levels of key regulators of glucose metabolism (hexokinase II and voltage-dependent anion channels). The hexokinase II dissociates from the mitochondria and Bax translocates to the mitochondria, which in turn leads to metabolic stress-induced apoptosis. (3) Inhibin inhibits the growth of prostate cancer cells by augmenting the antiproliferative effects of activin. Inhibin binds to its receptor (inhibin-binding protein) there by having an additive inhibitory effect to that of activin. Inhibin is downregulated in high-grade prostate cancer, and the functional deletion of its gene results in development of gonadal tumors. On the contrary, inhibin prevents the inhibition of prostate cancer cells by antagonizing the antiproliferative effects of activin by acting in a 'dominant-negative mechanism' with the activin receptor. Inhibin binds to activin receptor type 2 preventing the recruitment of activin receptor type 1. This antagonism of activin action by inhibin is facilitated by betaglycan. Inhibin binds with betaglycan blocking activin access to the activin receptors. (4) Promoting dissemination of tumor cells by follistatin (i) indirectly by initiating an antiapoptotic effect in glucose-deprivation conditions and inhibiting activin receptor type 2-mediated signaling pathways. During glucose deprivation, follistatin translocates and accumulates in the nucleoli of tumor cells. The overexpression of follistatin in the nucleoli negatively regulates ribosomal RNA synthesis and ribosome biogenesis delaying glucose deprivation-induced apoptosis. In the presence of follistatin, the tumor cells become resistant to glucose deficiency contributing to tumor progression. (ii) Directly by interacting with nuclear pro-angiogenic angiogenin thus facilitating proliferation and angiogenesis of tumor cells. (iii) By modulating the activity of the bone morphogenic protein-7, which regulates senescence of prostate cancer stem-like cells via the p38/p21/N-myc downstream-regulated gene 1 signaling pathway. Follistatin binds and antagonizes the effects of bone morphogenic protein-7. (iv) Directly by inhibiting activin receptor type 2, which upregulates disintegrin and metalloproteinase domain-containing protein 15 (ADAM-15), which in turn leads to tumor cell detachment and tumor metastasis. The overexpression of ADAM-15 is strongly correlated with prostatic metastasis. The functions of follistatin, myostatin, activin and inhibin are regulated by activin receptors. In addition, activin receptors facilitate both tumor cell proliferation and apoptosis by regulating the expression of ADAM-15. Increased receptor signaling decreases the expression of ADAM-15 causing tumor cells to adhere to the endothelial cell matrix and proliferate. Conversely, a decrease in receptor signaling increases ADAM-15 expression causing tumor cells to detach from the endothelial cell matrix, which can lead to apoptosis or metastasis.
Proposed Signaling Pathways
Although emerging data provide strong evidence of decreased prostate cancer risk following physical activity, the fundamental question still remains unanswered 'what are the signaling pathways associating physical activity and prostate cancer at the molecular and cellular level?' As discussed elsewhere in this review, the skeletal muscle produces and secretes numerous proteins. In order to elucidate the biological mechanisms associating physical activity and prostate cancer risk, it is important to identify and analyze these proteins and understand their role in the processes of normal and aberrant growth and development of the prostate gland. In addition, these proteins are altered following physical activity in healthy individuals. Understanding how physical activity alters these proteins and how they control key cellular processes might indicate their role in preventing prostate cancer. In this review, we have focused on the proteins that affect prostate growth and development and that have been shown to influence the progression of prostate cancer. Under discussion therefore, are myostatin (a myokine), follistatin, activin, inhibin and their receptors (activin receptors).
Myostatin, Activin, Inhibin and Activin Receptors
Myostatin, activin and inhibin belong to the transforming growth factor β superfamily. Myostatin is predominantly expressed in skeletal muscle cells but at low levels in cardiac muscle and adipose tissue. Its activity is controlled by transcription and posttranslational modification. It is stored as a latent complex in the extracellular space and bound to propeptide that prevents it from binding to the receptor. Other circulating proteins such as follistatin and the follistatin-like proteins also bind and inhibit myostatin. Activin is expressed in gonadal tissues where it stimulates follicle stimulating hormone (FSH) biosynthesis and secretion in the pituitary. There are three isoforms of activin: activin A (βAβA), activin B (βBβB), and activin AB (βAβB). Activin A is the major form. Its activity is regulated via its latent complex where its propeptide remains associated and prevents its binding to activin receptors or by follistatin, which binds and neutralizes its activity. Inhibin is produced in numerous organs such as the gonads, pituitary gland, placenta and corpus luteum. It downregulates FSH synthesis and inhibits FSH secretion. Two forms of inhibin exist: inhibin A (αβA) and inhibin B (αβB). The signaling of myostatin, activin and inhibin is modulated by activin receptors. The ligand (myostatin, activin or inhibin) binds to the activin receptors triggering a downstream signaling cascade that translocates Smad2/3 into the nucleus and leading to changes in gene expression. There are two types of activin receptors: type 1 and type 2. There are three subtypes of the type 1 receptor (1A, 1B and 1C) and two subtypes of the type 2 receptor (2A and 2B). Each subtype of the type 1 receptor binds to a specific type II receptor–ligand complex (Figure 3).
(Enlarge Image)
Figure 3.
A hypothetical model to explain how physical activity through different proteins is linked to prostate cancer. AR1=activin receptor type 1, AR2=activin receptor type 2, BG=betaglycan, co-SMAD=common-mediator Smad, InhBP=inhibin-binding protein, RSMAD=receptor-regulated Smads, rDNA=ribosomal DNA. (A): Under glucose-deprived conditions, follistatin expression is increased and accumulates in the nucleolus. It then binds to ribosomal DNA and represses ribosomal RNA synthesis lowering energy consumption in cancerous cells, thus promoting cancer cell survival. (B): It is not known how follistatin accumulates in the nucleolus. It may permeate the tumor cell membrane and the nuclear membrane into the nucleolus. (C): Mitochondrial-dependent apoptosis; myostatin promotes the translocation of Bax from cytosol to mitochondria resulting in metabolic stress-induced apoptosis. (D): Activin or myostatin binds to AR2, which recruits and phosphorylates AR1 activating the ligand. AR1 phosphorylates RSMAD in the presence of SARA, which binds to coSMAD and translocates to the nucleus where it binds to transcription factors causing DNA transcription. This pathway is inhibited by SMAD 6 or 7. (E): Activin or myostatin might regulate apoptosis or induce growth arrest: (i) transcriptionally by regulating apoptosis-related genes, such as XIAP, Bcl-2/Bcl-xl or Bim; (ii) through non-canonical pathways, such as JNK and Akt signaling, leading to the phosphorylation and activation of the pro-apoptotic molecules; or (iii) activin may induce dormancy of prostate cancer cells by facilitating growth arrest where cells are blocked in the G0/G1 or G2/M phases of cell cycle. (F): The binding of inhibin to the inhibin receptor (inhibin-binding protein) leads to recruitment of the AR1. This enables inhibin to inhibit growth of prostate cancer cells by complementing the antiproliferative effects of activin (inhibin has an additive inhibitory effect to that of activin). (G): Inhibin binds to AR2 preventing the recruitment of AR1. This is facilitated by betaglycan. Inhibin binds with betaglycan blocking activin access to the activin receptor. Inhibin prevents the inhibition of prostate cancer cells by antagonizing the antiproliferative effects of activin by acting in a dominant-negative mechanism with the activin receptor. (H): Follistatin can bind to activin or myostatin preventing it from binding to its receptor and antagonizing their action (apoptosis or growth arrest). For the follistatin–myostatin complex, follistatin neutralizes myostatin activity. For the follistatin–activin complex, follistatin neutralizes activin activity or mops it out of circulation by lysosomal breakdown.
Follistatin is expressed in nearly all human tissues and the highest concentrations can be found in the ovary and skin. Endothelial cells, macrophages and monocytes have also been suggested as alternative sources of follistatin. Follistatin acts as a ligand inhibitor that binds and inhibits myostatin and activin, therefore interfering with functions ascribed to both proteins. Follistatin is also part of the inhibin–activin–follistatin axis, which has an important role in the human reproductive system. There are three isoforms of follistatin—FLS315 (from pre-FLS344), FLS288 (from pre-FLS317) and FS303 (intermediate). The FLS315 variant is predominant, while the FLS288 isoform accounts for <5% of the encoded mRNA. These isoforms are widely present and differentially expressed in human tissues (Figure 3).
Myostatin, Activin, Inhibin and Activin Receptors in the Prostate Gland
Myostatin inhibits muscle growth and is predominantly expressed in skeletal muscle cells. It is not known whether this protein is present in the prostate gland. However, given its role of negatively regulating muscle growth and in cancer-induced muscle wasting it may be present. The human prostate gland synthesizes follistatin, activin and inhibin. Follistatin is expressed in the basal epithelial cells and in the fibroblastic stromal, whereas activin and inhibin are predominantly localized to the epithelium. The prostate gland has been shown to express activin receptors, suggesting that these proteins have a local role in the functioning of the prostate gland. The follistatin–activin–inhibin system controls the physiological growth and functions of the prostate gland in a paracrine–autocrine manner. The proteins regulate the growth of normal prostatic epithelial cells in a paracrine manner between stromal and epithelial cells. In malignancy, epithelial tumor cell growth is regulated in an autocrine manner and may involve a different interplay between these proteins.
Myostatin, Activin, Inhibin and Activin Receptors in Prostate Cancer
The mechanisms by which follistatin, myostatin, activin and inhibin facilitate proliferation, dissemination, inhibition or apoptosis of human prostate cancer cells have not been fully elucidated. However, this could be explained by (Figure 3): (1) Induction of growth arrest of prostate cancer cells thus limiting proliferation of the tumor cells at the new site. This process is facilitated by activin, which blocks the cells in the G0/G1 or G2/M phases of cell cycle. For this process to occur, activin must bind to the activin receptor. The binding of activin to its receptor can be prevented by follistatin, which antagonizes the effects of activin by binding to activin and preventing this interaction and downstream effect therefore driving proliferation and dissemination of the cells. (2) Regulation of prostate cancer cell growth or death indirectly through the regulation of energy metabolism by myostatin. Myostatin induces a metabolic change from oxidative phosphorylation to glycolysis in tumorous cells leading to mitochondrial-dependent apoptosis. Myostatin affects the levels of key regulators of glucose metabolism (hexokinase II and voltage-dependent anion channels). The hexokinase II dissociates from the mitochondria and Bax translocates to the mitochondria, which in turn leads to metabolic stress-induced apoptosis. (3) Inhibin inhibits the growth of prostate cancer cells by augmenting the antiproliferative effects of activin. Inhibin binds to its receptor (inhibin-binding protein) there by having an additive inhibitory effect to that of activin. Inhibin is downregulated in high-grade prostate cancer, and the functional deletion of its gene results in development of gonadal tumors. On the contrary, inhibin prevents the inhibition of prostate cancer cells by antagonizing the antiproliferative effects of activin by acting in a 'dominant-negative mechanism' with the activin receptor. Inhibin binds to activin receptor type 2 preventing the recruitment of activin receptor type 1. This antagonism of activin action by inhibin is facilitated by betaglycan. Inhibin binds with betaglycan blocking activin access to the activin receptors. (4) Promoting dissemination of tumor cells by follistatin (i) indirectly by initiating an antiapoptotic effect in glucose-deprivation conditions and inhibiting activin receptor type 2-mediated signaling pathways. During glucose deprivation, follistatin translocates and accumulates in the nucleoli of tumor cells. The overexpression of follistatin in the nucleoli negatively regulates ribosomal RNA synthesis and ribosome biogenesis delaying glucose deprivation-induced apoptosis. In the presence of follistatin, the tumor cells become resistant to glucose deficiency contributing to tumor progression. (ii) Directly by interacting with nuclear pro-angiogenic angiogenin thus facilitating proliferation and angiogenesis of tumor cells. (iii) By modulating the activity of the bone morphogenic protein-7, which regulates senescence of prostate cancer stem-like cells via the p38/p21/N-myc downstream-regulated gene 1 signaling pathway. Follistatin binds and antagonizes the effects of bone morphogenic protein-7. (iv) Directly by inhibiting activin receptor type 2, which upregulates disintegrin and metalloproteinase domain-containing protein 15 (ADAM-15), which in turn leads to tumor cell detachment and tumor metastasis. The overexpression of ADAM-15 is strongly correlated with prostatic metastasis. The functions of follistatin, myostatin, activin and inhibin are regulated by activin receptors. In addition, activin receptors facilitate both tumor cell proliferation and apoptosis by regulating the expression of ADAM-15. Increased receptor signaling decreases the expression of ADAM-15 causing tumor cells to adhere to the endothelial cell matrix and proliferate. Conversely, a decrease in receptor signaling increases ADAM-15 expression causing tumor cells to detach from the endothelial cell matrix, which can lead to apoptosis or metastasis.
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