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Role of Insulin in the pathogenesis of prostate cancer

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Role of Insulin in the pathogenesis of prostate cancer Dr. H. Nandeesha Dept: of Biochemistry PKMC & RI Puducherry Introduction: Prostate cancer Insulin ... – PowerPoint PPT presentation

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Title: Role of Insulin in the pathogenesis of prostate cancer


1
Role of Insulin in thepathogenesis of prostate
cancer
  • Dr. H. Nandeesha
  • Dept of Biochemistry
  • PKMC RI
  • Puducherry

2
  • Introduction Prostate cancer
  • Insulin
  • Insulin as growth hormone
  • Experimental and clinical studies
  • Biochemical mechanisms

3
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.

4
Etiology
  • Family history
  • Alteration in sex hormones
  • High fat intake
  • Obesity
  • Inflammation
  • Exposure to cadmium

5
Insulin structure
6
Insulin receptor
extracellular
cytoplasmic
7
Mechanism of insulin action
  • Insulin IR
  • phosphorylation of IRS
  • IRS-1
    IRS-2
  • p21Ras
    PKB
  • MAP kinases
    SGK, aPKC
  • Growth
    Metabolism

GTPase
PI3-Kinases
8
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

9
Insulin resistance and cancer
  • Insulin resistance hyperglycemia
  • increases DNA synthesis of tumor cells
  • increases protein glycation
  • free radicals
  • cytokines
  • stimulate growth factors

10
Cancers associated with insulin resistance
  • Prostate
  • Breast
  • Pancreas
  • Liver
  • Colon
  • Bladder
  • Oral cavity

11
  • Experimental and clinical studies that link
    insulin and prostate cancer

12
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)

13
  • 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)

14
  • Mechanisms that link insulin and
  • Prostate cancer

15
  • Sympathetic nerve activity
  • Alters sex hormone metabolism
  • Activates IGF pathway
  • Stimulates signal transduction pathway
  • Alters lipid metabolism
  • Inflammation

16
Sympathoexcitatory effect of insulin
  • Insulin stimulate ventromedial
  • nucleus of
    hypothalamus
  • sympathetic
    activity
  • catecholamines
  • reduces apoptosis
    in
    prostate cells

17
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

18
IGF pathway
  • IGF regulates physiological and pathological
    growth process
  • Plays a key role in cellular metabolism,
    differentiation, proliferation, transformation
    and apoptosis

19
  • 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

20
  • Hyperinsulinemia synthesis of IGF-1

  • synthesis of IGFBP

  • bioactivity of IGF-1

  • cancer risk

21
  • Insulin receptor share homology with IGF receptor
  • Insulin bind to IGF receptor, activate IGF
    signaling pathway and stimulate cancer growth

22
Signal transduction mechanism
  • Insulin binds with insulin
    receptor
  • stimulate
    adenyl cyclase
  • production of
    c-AMP
  • induces
    mitogenic and
  • anti apoptotic
    factors

23
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

24
Inflammation
  • Insulin resistance
  • inflammatory markers (cytokines)
  • cell and genome damage
  • promote cellular turnover
  • cell replication
  • angiogenesis
  • tumor growth and progression

25
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

26
THANK YOU
WISH YOU ALL A HAPPY NEW YEAR 2009
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