Role of Insulin in the pathogenesis of prostate cancer

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Role of Insulin in thepathogenesis of prostate
cancer

• Dr. H. Nandeesha
• Dept of Biochemistry
• PKMC RI
• Puducherry

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• Introduction Prostate cancer
• Insulin
• Insulin as growth hormone
• Experimental and clinical studies
• Biochemical mechanisms

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Prostate cancer

• Most common non-cutaneous malignancy in aging
  men.
• Second leading cause of cancer deaths among men.
• Constitutes about 30-40 of male genital tract
  cancers.

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Etiology

• Family history
• Alteration in sex hormones
• High fat intake
• Obesity
• Inflammation
• Exposure to cadmium

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Insulin structure
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Insulin receptor
extracellular
cytoplasmic
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Mechanism of insulin action

• Insulin IR
• phosphorylation of IRS
• IRS-1
  IRS-2
• p21Ras
  PKB
• MAP kinases
  SGK, aPKC
• Growth
  Metabolism

GTPase
PI3-Kinases
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Growth promoting effects of insulin

• Insulin regulates cell proliferation,
  differentiation and apoptosis
• Continuous Insulin infusion
• enhance glucose uptake and utilization
• facilitate neonatal growth
• (Zylberberg et al Neonatal Netw 2001)
• Enhances the production of growth factors

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Insulin resistance and cancer

• Insulin resistance hyperglycemia
• increases DNA synthesis of tumor cells
• increases protein glycation
• free radicals
• cytokines
• stimulate growth factors

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Cancers associated with insulin resistance

• Prostate
• Breast
• Pancreas
• Liver
• Colon
• Bladder
• Oral cavity

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• Experimental and clinical studies that link
  insulin and prostate cancer

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Insulin and prostate cancer

• Insulin receptors have been identified on
  prostate epithelial cells
• (Carmena et al, Cell Biochem Fun,1986)
• In-vitro expts have demonstrated need of insulin
  for prostate growth
• (Mckeehan et al, Can Res, 1984)

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• High insulin levels were reported in patients
  with BPH and prostate cancer
• (Nandeesha et al, Clin Chim Acta, 2006)
• (Nandeesha et al, Acta Physiol Hungarica,
  2008)
• Insulin could be used as a marker of prostate
  cancer prognosis and tumor aggressiveness
• (Hammarsten et al, Eur J Cancer, 2005)

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• Mechanisms that link insulin and
• Prostate cancer

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• Sympathetic nerve activity
• Alters sex hormone metabolism
• Activates IGF pathway
• Stimulates signal transduction pathway
• Alters lipid metabolism
• Inflammation

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Sympathoexcitatory effect of insulin

• Insulin stimulate ventromedial
• nucleus of
  hypothalamus
• sympathetic
  activity
• catecholamines
• reduces apoptosis
  in
  prostate cells

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Sex hormone metabolism

• Insulin enhances transcription of genes involved
  in the metabolism of sex hormones
• Reduces sex hormone binding globulin
• Increases the amount of androgen and estrogen
  entering prostate cells

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IGF pathway

• IGF regulates physiological and pathological
  growth process
• Plays a key role in cellular metabolism,
  differentiation, proliferation, transformation
  and apoptosis

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• IGF-1 is synthesized in liver along with its
  binding proteins (IGFBP-1,2,3,4,5,6)
• IGF-1 is implicated directly and IGFBP-3
  inversely in cancer growth, survival and
  progression.
• IGF-1 activates IGF receptor inducing in
  mitogenic and antiapoptotic effects on normal and
  malignant cells

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• Hyperinsulinemia synthesis of IGF-1
• 
  synthesis of IGFBP
• 
  bioactivity of IGF-1
• 
  cancer risk

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• Insulin receptor share homology with IGF receptor
• Insulin bind to IGF receptor, activate IGF
  signaling pathway and stimulate cancer growth

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Signal transduction mechanism

• Insulin binds with insulin
  receptor
• stimulate
  adenyl cyclase
• production of
  c-AMP
• induces
  mitogenic and
• anti apoptotic
  factors

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Dyslipidemia

• Insulin resistance high TG
• low
  HDL-Cholesterol
• Low HDL
  LDL-Cholesterol
• oxidative
  modification of LDL
• increases
  intracellular calcium
• cell proliferation activate
  protein kinase C

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Inflammation

• Insulin resistance
• inflammatory markers (cytokines)
• cell and genome damage
• promote cellular turnover
• cell replication
• angiogenesis
• tumor growth and progression

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Conclusion

• Hyperinsulinemia is a risk factor in the
  development of prostate cancer
• Clinical studies are needed to confirm whether
  reduction in insulin levels reduces cancer risk
  

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THANK YOU
WISH YOU ALL A HAPPY NEW YEAR 2009