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

Figure 1

Insulin receptor (INSR) belongs to a family of receptor tyrosine kinases that includes the receptor for insulin-like growth factor 1 (IGF-1R). Many tumour types have upregulated expression of IGF-1R, INSR, and potentially hybrid INSR/IGF-1Rs which facilitate increased activation of mitogenic, prosurvival and protein synthesis pathways following activation by of ligands insulin, IGF-1 or IGF-2. IGF-1 can bind the INSR with 2.5% the efficiency of insulin. Insulin, at physiological levels, will not activate the IGF-1R. Insulin and IGF-1 can activate signalling with varying potency through the hybrid INSR/IGF-1R. IGF2 is able to signal through each of the INSR, IGF-1R, and hybrid receptor (Hybrid R). Ligand binding to the INSR and IGF-1R activate numerous downstream pathways including phosphatidylinositol 3 kinase (PI3K)/Akt and Ras/MAPK pathways with many well-characterised downstream effects including increased glucose metabolism, inhibition of apoptosis (e.g., via FOXO and BAD-mediated pathways), and stimulation of cell proliferation (e.g., via mammalian target of rapamycin; mTOR). Reciprocal feedback regulation occurs in prostate cancer cells between the AR signalling and signalling through the PI3K-AKT-mTOR pathway. Unfettered activity through this pathway, associated with the common PTEN mutation, inhibits AR signalling and suggests a possible pathway to androgen-independent growth of prostate tumours. AMP-activated protein kinase (AMPK) is a potentially bifunctional modulator in prostate cancer cells. Activation of AMPK modulates insulin signalling by negatively regulating mTOR control of protein synthesis and halting cell proliferation. AMPK activation also promotes fatty acid oxidation and downregulates expression of SREBP and activity of acetyl-CoA carboxylase (ACC) resulting in decreased fatty acid synthesis. However, AMPK has complex regulation in prostate cancer cells and may potentiate increased proliferation and migration when activated downstream of the AR under the control of AR responsive regulator calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2). AR directly regulates CAMKK2 and upregulates AMPK which mediates AR-induced migration and invasion in a CAMKK2-dependent manner. In studies where metformin activation of AMPK results in cessation of cancer cell growth, signalling is thought to be through LKB-1 tumour suppressor; therefore, competition for AMPK signalling via LKB1 stimulation versus AR-mediated CAMKK2 activation could result in altered functional outcomes. DHT, dihydrogen testosterone; AR, androgen receptor; ARE, androgen response element; MAPK, mitogen-activated protein kinase.