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Abstract

Recent years have witnessed a resurgence in tumor metabolism research. Cancer cells are known to exhibit multiple distinct aberrations in energy-utilization that help them sustain rapid growth and proliferation, as well as cope with harsh microenvironment conditions, such as limited nutrient availability and oxygenation. Amplified growth factor and oncogenic signaling have been implicated in the observed metabolic reprogramming in cancers, and thus, drugs that target these signaling aberrations have also been shown to impact metabolism. Furthermore, several drugs have been developed or repurposed to interfere with metabolic processes in transformed cells. In this thesis, the results of my investigations into the ability of 1,25- dihydroxyvitamin D3 [1,25(OH)2D3] (also referred to as calcitriol)—the hormonally active form of vitamin D3—to influence metabolic pathways in different cancer models are presented. Using prostate cancer cell lines with different androgen sensitivities, as well as breast cancer cell lines representing different molecular subtypes, it is shown that 1,25(OH)2D3 is a major regulator of energy-utilization and glucose-sensing networks in these cancer cells. Detailed investigation of cellular metabolism using biosensor technology, GC/MS-based metabolomics, RT-qPCR gene expression analyses, enzymatic activity assays, FACS analyses, and immunoblotting, illustrates that 1,25(OH)2D3 induces global rewiring of glucose-metabolizing pathways, as well as modulates energy-related signaling molecules including AMP-activated protein kinase and thioredoxin-interacting protein (TXNIP). My results also show, that in contrast to the long-standing association between TXNIP and calcitriol, the former is not universally regulated by the latter in cancer cell lines of various tissue origins, and that the canonical regulation is subject to glucose-availability. In conclusion, I like to propose that regulation of onco-metabolism is a mechanism through which calcitriol induces its anti-cancer effects, and argue that continued investigations into this theme would elucidate ways to improve the molecule’s therapeutic potential.