1 research outputs found
Reprogramming of Basic Cellular Metabolism by Vitamin D in Tumor Cells
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