Prostate Cancer Metabolism: Effects of β2-Adrenergic Receptor Knockdown in LNCaP Cells

Abstract

Prostate cancer (PCa) is the second most frequently occurring cancer in men worldwide. Androgen deprivation is the desired therapy for patients with recurring disease or metastatic cancer. Over time the disease relapses as a castration-resistant prostate cancer (CRPC) with grave prognoses. Low levels of the β2-adrenergic receptor (ADRB2) in prostate tumors has been correlated with shorter time to PCa progression and a faster evolvement of CRPC. The roles of the ADRB2 in determining clinical outcome in patients is unclear, but proposed mechanisms involve activation of the androgen receptor, the core metabolic regulator of prostate metabolism.Metabolic profiling, which is increasingly acknowledged as an important field in cancer research, can help to find clues about factors effecting the clinical outcome of PCa. Stable ADRB2 knockdown LNCaP cells were made, and their metabolism relative to cells with non-targeting knockdown was investigated in a metabolomic and non-metabolomic manner. ADRB2 knockdown cells were shown to inherit a higher glycolytic flux, coupled with lower oleic-acid oxidation. 1H NMR analyses revealed higher levels of the amino acids alanine, glutamine, glutamate and glycine in ADRB2 knockdowns. Transcriptomic analyses revealed increased expression of genes involved in lipid metabolism, steroidogenesis and genes regulating the amount and distribution of membrane lipids. Significantly lower mRNA-levels of the androgen-inactivation UGT2B-family of genes was found in the ADRB2 knockdowns.The information presented in this thesis indicates that low-ADRB2 LNCaP cells present a distinct metabolism compared to control cells. Several of the metabolic alterations observed in ADRB2 knockdown LNCaP cells have been found to be malignant markers in late-stage prostate cancers. The results call more studies to shed light on whether these changes can explain how the ADRB2 is correlated to progression in PCa.