**2. Androgen-dependent and androgen-independent prostate cancer**

Human prostate is a walnut shaped, fibromuscular organ located beneath the urinary bladder and is made-up of several glandular and non-glandular components that are tightly fused together within a common capsule [9]. It is an exocrine gland functioning in secretion of complex proteolytic solution into the urethra during ejaculation which is important for sperm motility and nourishment. The growth and function of the prostate are regulated by androgens. The growth and development of normal prostate requires functioning androgen signaling pathway, which is regulated by hypothalamic-pituitary gonadal axis. Androgens (includes testosterone and DHT) are responsible for the male secondary sexual characteristics. Testosterone is synthesized in the testes and released into the circulation in response to specific hormonal signals regulated by GnRH, FSH, and LH. Testosterone is transported by steroid hormone binding globulin (SHBG) to the prostate, where it is converted by 5α-reductase to its active metabolite 5α-dihydrotestosterone (DHT).

In the prostate, androgens mediate their effects *via* high affinity to the androgen receptor (AR), a nuclear transcription factor that controls expression of genes involved in growth, differentiation, homeostatsis, and apoptosis. Receptor for steroid and thyroid hormones are mostly cytoplasmic/nuclear receptors and hormonereceptor complex binding to the promoter regions of responsive genes and stimulate or inhibit transcription from those genes. Nuclear receptors are ligand-inducible transcription factors that mediate the signals of a broad variety of fat-soluble hormones, including the steroid and vitamin D3 hormones, thyroid hormones retinoids.

**165**

*Combinatorial Drug Therapy with Phytochemicals as Adjuvants in Prostate Cancer Management*

Upon ligand binding, AR translocates to the nucleus, binds to DNA recognition sequences, and activates transcription of genes involved in cell proliferation, apoptosis, and differentiation [10]. Androgens are involved in the development and progression of prostate cancer [11] regulating the AR. During this phase the tumors are referred to as androgen sensitive or dependent. The most common therapies done with prostate cancer patients are androgen deprivation therapy removing testicles partially or completely in addition to administration of drugs inhibiting LHRH secre-

tion and anti-androgen therapy blocking the androgen receptor interaction.

of androgen levels [12]. The AR signaling pathway continues to be active in hormone resistant prostate cancer (HRPC) and can inappropriately activate transcription [13]. Recent studies show that cancer progression and metastasis lead to alteration in the androgen receptor pathway genes with transition of prostate cancer from the androgen dependent to independent stage [14]. Mutations in the ligandbinding domain alter the specificity of the AR enhancing the binding of estrogens, progesterone, and anti-androgens; and thereby decreasing its dependency on androgens while stimulating cell growth. In addition to AR mutations, a variety of growth factors, including insulin-like growth factor I, epidermal growth factor, and keratinocyte growth factor, can activate androgen-responsive genes *via* the AR, suggesting that androgen independence which occurs due to the over expression of growth factors in the local environment [15]. There are multiple evidences suggesting that estrogens are involved in prostate carcinogenesis. In worldwide the African-Americans have the higher risk of prostate cancer with elevated levels of serum estrone and estradiol levels even in healthy young men [16]. CCDC62/ERAP75 is a new co-activator of ER and this protein is mainly present in the nucleus and widely expressed in many prostate cancer cell lines (PC-3, DU145, LNCaP, 22Rv1) than in

Prostate cancer can evolve into castration resistant cancers which is independent

The inappropriate expression of the growth inhibitory factors appears to contribute to prostate cancer progression. Epidermal growth factor (EGF) promotes chemo-migration of metastatic prostate cancer cells to lymph node and medullary bone sites [18]. In insulin signaling pathway, the ligand insulin binds to its receptor followed by tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase. Several studies suggested that alteration in the IGF signaling axis is associated with an increased risk of prostate cancer [19]. Signal transduction proteins interact with IRS including GRB2. GRB2 is a part of the cascade including SOS, RAS, RAF, and MEK that leads to activation of MAPK and

In AKT signaling pathway, PTEN is a regulator which is down regulated to protect the cell from tumor growth. The phosphatase activity on phosphatidylinositol 3,4,5-triphosphate allows dephosphorylation of PIP3 to PIP2. The PIP2 inhibits the P13K which is the membrane bound domain. When the phosphatase activity is lost, P13K transfers its phosphate group to PDK1 and PDK2 which in turn causes phosphorylation of AKT protein and regulatory amino acids Ser473 and Thr308. This leads to activation of MDM2, P21, CASP9, mTOR genes leading to apoptosis inhibition, tumor growth, etc. Smad3 gene plays a key role in prostate cancer serving as an essential mediator of most Smad-dependent TGF-beta responses, including control of gene expression, cell growth, apoptosis, and tumor suppression. Deregulated/ enhanced expression and activation of AR in prostate carcinomas may intercept the tumor suppressor function of TGF-β through transcriptional suppression of Smad3.

*DOI: http://dx.doi.org/10.5772/intechopen.86157*

the normal prostate epithelial cells (BPH-1) [17].

**3. Molecular regulations in prostate cancer**

mitogenic response in the form of gene transcription.

### *Combinatorial Drug Therapy with Phytochemicals as Adjuvants in Prostate Cancer Management DOI: http://dx.doi.org/10.5772/intechopen.86157*

Upon ligand binding, AR translocates to the nucleus, binds to DNA recognition sequences, and activates transcription of genes involved in cell proliferation, apoptosis, and differentiation [10]. Androgens are involved in the development and progression of prostate cancer [11] regulating the AR. During this phase the tumors are referred to as androgen sensitive or dependent. The most common therapies done with prostate cancer patients are androgen deprivation therapy removing testicles partially or completely in addition to administration of drugs inhibiting LHRH secretion and anti-androgen therapy blocking the androgen receptor interaction.

Prostate cancer can evolve into castration resistant cancers which is independent of androgen levels [12]. The AR signaling pathway continues to be active in hormone resistant prostate cancer (HRPC) and can inappropriately activate transcription [13]. Recent studies show that cancer progression and metastasis lead to alteration in the androgen receptor pathway genes with transition of prostate cancer from the androgen dependent to independent stage [14]. Mutations in the ligandbinding domain alter the specificity of the AR enhancing the binding of estrogens, progesterone, and anti-androgens; and thereby decreasing its dependency on androgens while stimulating cell growth. In addition to AR mutations, a variety of growth factors, including insulin-like growth factor I, epidermal growth factor, and keratinocyte growth factor, can activate androgen-responsive genes *via* the AR, suggesting that androgen independence which occurs due to the over expression of growth factors in the local environment [15]. There are multiple evidences suggesting that estrogens are involved in prostate carcinogenesis. In worldwide the African-Americans have the higher risk of prostate cancer with elevated levels of serum estrone and estradiol levels even in healthy young men [16]. CCDC62/ERAP75 is a new co-activator of ER and this protein is mainly present in the nucleus and widely expressed in many prostate cancer cell lines (PC-3, DU145, LNCaP, 22Rv1) than in the normal prostate epithelial cells (BPH-1) [17].
