Location of Repository

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

By Jennifer H. Gunter, Amy A. Lubik, Ian McKenzie, Michael Pollak and Colleen C. Nelson

Abstract

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer

Topics: Review Article
Publisher: Hindawi Publishing Corporation
OAI identifier: oai:pubmedcentral.nih.gov:3324133
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Preview

    Citations

    1. (2007). A .W .H s i n g ,L .C .S a k o d a ,a n dS .C h u aJ r . ,“ O b e s i t y ,m e t a -bolic syndrome, and prostate cancer,”
    2. (2002). A history of prostate cancer treatment,”Nature Reviews Cancer,vol.2,no.5,pp.389–396,
    3. (2011). a n a ,B .C .F a m ,M .V .C l a r k e ,T .P . S .P a n g ,J .D .Z a j a c
    4. (2006). a n dO .N .W i t t e ,“ P r o g r e s s i o no fp r o s t a t ec a n c e rb ys y n e r g y of AKT with genotropic and nongenotropic actions of the androgen receptor,”
    5. (2011). A pilot study on the transcriptional response of androgen- and insulinrelated genes in peripheral blood mononuclear cells induced bytestosteroneadministrationinhypogonadal men,”Journal of Biological Regulators and Homeostatic Agents,
    6. (2011). A.A.Lubik,J.H.Gunter,S.C.Hendyetal.,“Insulinincreases de novo steroidogenesis in prostate cancer cells,”
    7. (1995). Abiraterone and increased survival in metastatic prostate cancer,” The New England
    8. (2007). Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism,”
    9. (2008). Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer,”
    10. (2010). Ambroisine et al., “Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer,”
    11. (2004). AMP-activated protein kinase activators can inhibit the growthofprostatecancercellsbymultiplemechanisms,”Biochemical and
    12. (2007). AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy,”
    13. (2010). AMPK exerts dual regulatory effects on the PI3K pathway,”
    14. (2009). Androgen deprivationtherapyforthetreatmentofprostatecancer:con-Advances in Urology 9 sider both benefits and risks,”
    15. (2004). Androgen receptor cross-talk with cell signalling pathways,”
    16. (2001). Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen,”
    17. (2002). Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein,”
    18. (2010). B.S.Taylor,N.Schultz,H.Hieronymusetal.,“Integrativegenomic profiling of human prostate cancer,”
    19. (1997). Bergstr¨ om et al., “Body size and prostate cancer: a 20-year follow-up study among 135 006 Swedish construction workers,”
    20. (2005). Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis,”
    21. (2011). Body fatness and sex steroid hormone concentrations
    22. (2001). Body mass index, height, and prostate cancer mortality in two large cohorts of adult men
    23. (2011). CaM kinase kinase β-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells,”
    24. (2010). Care of the cancer survivor: metabolic syndrome after hormone-modifying therapy,”
    25. (2011). Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth,”
    26. (2010). Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European male ageing study,”
    27. (2010). Clusterin facilitates COMMD1 and I-κB degradation to enhance NF-κB activity in prostate cancer cells,”
    28. (2007). Cooperative interactionsbetweenandrogenreceptor(AR)andheat-shock protein 27 facilitate
    29. (2011). D.K.Nomura,D.P.Lombardi,J.W.Changetal.,“Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer,”
    30. (1994). Decreased testosterone and dehydroepiandrosterone sulfate concentrations are associated with increased insulin and glucose concentrations in nondiabetic men,”
    31. (2008). Diabetes mellitus and prostate cancer risk,”
    32. (2010). Diabetes mellitus, hyperglycaemia and cancer,”
    33. (2007). Differential regulation of clusterin and its isoforms by androgens in prostate cells,”
    34. (2004). Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer,” The New England
    35. (2011). Docosahexaenoic acid selectively induces human prostate cancer cell sensitivity to oxidative stress through modulation of NF-κB,”
    36. (2011). Does diabetes mellitus increase the risk of high-grade prostate cancer in patients undergoing radical prostatectomy?”
    37. (2010). Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study,”
    38. (2011). Essential fatty acids enhance free radical generation and lipid peroxidation to induce apoptosis of tumor cells,”
    39. (2009). expression and promotes growth of prostate cancer cells,”
    40. (2008). F o w k e ,C .M .M a t t h e w s ,M .S .B u c h o w s k ie ta l . , “Association between prostate-specific antigen and leptin, adiponectin,
    41. (2006). Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer,”
    42. (2010). Finasteride modifies the relation between serum C-peptide and prostate cancer risk: results from the prostate cancer prevention trial,”
    43. (2004). Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes,”
    44. (2004). G r u n d y ,H .B .B r e w e r ,J .I .C l e e m a n ,S .C .S m i t h
    45. (2004). Garc´ ıa-Berrocal et al., “Partial androgen deficiency in aging type 2 diabetic men and its relationship to glycemic control,”
    46. (2010). h a n g ,D .H .F a g a n ,X .Z e n g ,K .T .F r e e m a n ,D .S a c h d e v
    47. (1992). High-affinity insulin binding to an atypical insulin-like growth factor-I receptor in human breast cancer cells,”
    48. (2010). Hsp27 promotes insulin-like growth factor-I survival signaling in prostate cancer via p90Rsk-dependent phosphorylation and inactivation of BAD,” Cancer Research,v o l .7 0 ,n o .6 ,p p .
    49. (2006). Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy,”
    50. Hyperinsulinaemia: a prospective risk factor for lethal clinical prostate cancer,”
    51. (2008). Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome,”
    52. (2008). Hypothalamic CaMKK2 contributes to the regulation of energy balance,”
    53. (2003). Hypothalamic interleukin1β and tumor necrosis factor-α, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats,”
    54. (2004). I.Munir,H.W.Yen,D.H.Gelleretal.,“Insulinaugmentation of17α-hydroxylaseactivityismediatedbyphosphatidylinositol 3-kinase but not extracellular signal-regulated kinase-1/2 in human ovarian theca cells,”
    55. (2008). Insulin and insulin-like growth factor signalling in neoplasia,”
    56. (2010). Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy,”
    57. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease,”
    58. (1997). Insulin regulation of human ovarian androgens,” Human Reproduction,
    59. (2006). Insulin sensitivity during combined androgen blockade for prostate cancer,”
    60. (2010). Insulincarcinogenormitogen?Preclinicalandclinicalevidencefrom prostate, breast, pancreatic, and colorectal cancer research,”
    61. Interactions among peroxisome proliferator activated receptor-γ, insulin signaling pathways, and steroidogenic acute regulator yp r o t e i ni nh u m a no v a r i a nc e l l s ,
    62. (2004). Intermittent androgen deprivation therapy for prostate cancer,”
    63. (1992). Interrelation between plasma testosterone and plasma insulin in healthy adult men: the telecom study,”
    64. (2007). Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistantprostatecancer,”CancerResearch,vol.67,
    65. (2010). L e o n ,J .A .L o c k e ,H .H .A d o m a te ta l . ,“ A l t e r a t i o n s in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model,”
    66. Leptin stimulates fatty-acid oxidation by activating AMP-activated proteinkinase,”Nature,vol.415,no.6869,pp.339–343,2002.
    67. (2011). Low estradiol concentrations in men with subnormal testosterone concentrationsandtype2diabetes,”DiabetesCare,vol.34,no.8,pp. 1854–1859,
    68. (2011). Low levels of apolipoprotein A-I and HDL are associated with risk of prostate cancer
    69. (2008). Low testosterone levels are common and associated with insulin resistance in men with diabetes,”
    70. (2008). Lubik et al., “Androgen Levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer,”
    71. (2008). M o n t g o m e ry ,E .A .M o s t a g h e l ,R .V e s s e l l ae ta l . ,“ M a i n -tenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth,”
    72. (2009). M o r r i s ,a n dJ .M .M .E v a n s ,“ N e wu s e r so fm e t f o r m i na r ea t lowriskofincidentcancer:acohortstudyamongpeoplewith type 2 diabetes,” Diabetes Care,
    73. (2006). M.Stanbrough,G.J.Bubley,K.Rossetal.,“Increasedexpression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer,”
    74. (2006). Macdonald,andJ.B.Prins,“Adiponectin—akeyadipokineinthe metabolic syndrome,”
    75. (2005). Mechanisms of the development of androgen independence in prostate cancer,”
    76. (2011). Metabolic profiling of urine in young obese men using ultra performance liquid chromatography and Q-TOF mass
    77. (2010). Metabolic sequelae associated with androgen deprivation therapy for prostate cancer,”
    78. (2010). Metformin and other biguanides in oncology: advancing the research agenda,”
    79. Metformin and reduced risk of cancer in diabetic patients,”
    80. (2011). Metformin and the incidence of prostate cancer
    81. (2010). Metformin blocks the stimulative effect of a high-energy dietoncoloncarcinomagrowthinvivoandisassociatedwith reduced expression of fatty acid synthase,”
    82. (2007). Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells,”
    83. (2009). Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study,”
    84. (2010). New strategies inprostatecancer:targetinglipogenicpathwaysandtheenergy sensor
    85. (2009). o r i ,J .T .C h a n g ,E .R .A n d r e c h e ke ta l . ,“ A n c h o r a g e -independentcellgrowthsignatureidentifiestumorswithmetastatic potential,”
    86. (2010). o r i a r t y - K e l s e y ,J .E .H a r w o o d ,S .H .T r a v e r s
    87. (2006). Obesity and cancer risk: the role of the insulin-IGF axis,”
    88. (2008). Obesity and positive surgical margins by anatomic location after radical prostatectomy: results from the shared equal access regional cancer hospital database,”
    89. (2005). Obesity and prostate cancer,”
    90. (2007). Obesity and prostate cancer: epidemiology and clinical implications,”
    91. (2005). Obesity and the risk of prostate cancer,”
    92. (2008). Obesity in men: the hypogonadal-estrogen receptor relationship and its effect on glucose homeostasis,”
    93. (2007). Obesity, metabolic syndrome, and prostate cancer,”
    94. (2011). Paracrine and endocrine effects of adipose tissue on cancer development and progression,”
    95. (2010). PI3KAKT-mTOR pathway is dominant over androgen receptor signaling in prostate cancer cells,”
    96. (2008). Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancerspecific mortality in men with prostate cancer: a long-term survival analysis,”
    97. (2008). Predictive value of PTEN and AR coexpression of sustained responsiveness to hormonal therapy in prostate cancer—a pilot study,”
    98. (2011). Presence of the metabolicsyndromeisassociatedwithshortertimetocastration-resistant prostate cancer,”
    99. (2011). Prostate cancer risk in the Swedish AMORIS study: the interplay among triglycerides, total cholesterol, and glucose,”
    100. (2011). Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer,”
    101. (2005). Relationship between testosterone levels, insulin sensitivity, and mitochondrial function
    102. (2011). Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgenreceptorsplicevariants,”ClinicalCancerResearch,vol.
    103. (2005). Rho GTPases: biochemistry and biology,”
    104. (2001). Role of AMP-activated protein kinase in mechanism of metformin action,”
    105. (2011). Serum phospholipid fatty acids and prostate cancer risk: results from the prostate cancer prevention trial,”
    106. (2008). Serum prostatespecific antigen levels
    107. (2011). Serum total and HDL cholesterol and risk of prostate cancer,”
    108. (2003). Sex hormones, inflammation and the metabolic syndrome: a population-based study,”
    109. (2011). Sixteen years and counting: an update on leptin in energy balance,”
    110. (2009). Specific involvement of glycogen synthase kinase-3 in the function and activity of sex steroid hormone receptors reveals the complexity of their regulation,”
    111. (2009). t t a r d ,A .H .M .R e i d ,R .A ’ H e r ne ta l . ,“ S e l e c t i v e inhibition of CYP17 with abiraterone acetate is highly active inthetreatmentofcastration-resistantprostatecancer,”
    112. (2008). Targeting AMPK: a new therapeutic opportunity in breast cancer,”
    113. (2005). Testosterone administration suppresses adiponectin levels in men,”
    114. (2005). Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer,”
    115. (2004). Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men,”
    116. (2006). Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with β-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors,”
    117. (2011). The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis,”
    118. (2008). The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin
    119. (2003). The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin
    120. (2006). The effect of androgen deprivation therapy on fasting serum lipid and glucose parameters,” J o u r n a lo fU r o -logy,
    121. (2011). The influence of age on bioavailable and free testosterone is independent of body mass index and glucose levels,”
    122. (2009). The influence of glucose-lowering therapies on cancer risk
    123. (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling,”
    124. (2010). The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation,”
    125. (2010). The PI3K pathway as drug target in human cancer,”
    126. (2008). The role of exercise and PGC1α in inflammation and chronic disease,”
    127. (2009). The role of immunological system in the regulation of gonadoliberin
    128. (1993). Thomas,“Attenuatedluteinizinghormone(LH)pulseamplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men,”
    129. (2006). Transcriptional regulation by insulin: from the receptor to the gene,”
    130. (2009). Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy,”
    131. (2012). u b i n o w ,C .N .S n y d e r ,J .K .A m o ry ,A .N .H o o f n a g l e ,a n d
    132. (2011). u r t o l a ,H .S y v ¨
    133. (2011). Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity,”
    134. (2011). Urological aspects of the metabolic syndrome,”
    135. (2011). X.X.He,S.M.Tu,M.H.Lee,andS.C.Yeung,“Thiazolidinediones and metformin associated with improved survival of diabeticprostatecancerpatients,”AnnalsofOncology,vol.22,

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.