Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Pankaj K Singh

MeSH Headings

Vitamin B6, Pancreatic Cancer, One-carbon metabolism, SHMT

Abstract

Cancer cells rely on altered metabolism to support their uncontrolled proliferation under harsh conditions. Understanding the mechanisms of how metabolic alterations support tumor growth may provide a way to enhance current therapies. Vitamins are micronutrients that our body needs in small quantities but are essential for health maintenance. A number of metabolic processes relevant to cancer initiation and progression are also regulated by vitamins. Here, our studies showed that pancreatic ductal adenocarcinoma (PDAC) cells display an aberrant metabolism of vitamin B6 (VB6) to support their fast proliferation. VB6 was highly demanded and rapidly metabolized by PDAC cells. Depletion of VB6 restricted PDAC cell dividing in vitro and KPC (murine pancreatic cancer cells that were derived from genetically engineered KrasG12D/+; p53R172H/+; Pdx1-Cretg/+ (KPC) mouse models) tumor growth in vivo. Mechanical studies indicated that VB6-dependent one-carbon metabolism supported PDAC proliferation. VB6 depletion reduced the intracellular concentrations of key one-carbon metabolites that are needed for cell division. Blockade of the one-carbon metabolic pathway recapitulated VB6 deficiency effects. Supplement of downstream products of one-carbon pathway rescued VB6 depletion-induced proliferation blockage. While knockdown of VB6-dependent enzymes SHMT1/2 inhibited PDCA cell proliferation and blocked the pro-dividing effect of VB6. Taken together, our study implies that the VB6 coordinates multiple metabolic activities that are critical for cancer maintaining cell division. Inhibitors of the one-carbon metabolic pathway, by simultaneously attenuating the pro-proliferative effect of VB6, could become useful anti-PDAC agents.

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