Muqit Essani
Pronouns:
Research Mentor(s): Yatrik Shah
Research Mentor School/College/Department: Molecular & Integrative Physiology / Medicine
Program: UROPF
Session: Session 6 (3:40pm – 4:30pm)
Authors: Muqit Essani, Chesta Jain, Yatrik Shah
Abstract
Iron is a crucial micronutrient required by almost all living cells to carry out important cellular functions such as DNA replication, protein synthesis, ATP synthesis etc. Cancer cells are rapidly dividing cells that also require large amounts of iron to maintain proliferation. Multiple studies have shown that limiting iron availability in the cancer cells limits their growth and reduces tumor burden in mice. Similar to iron deficiency iron, excess is also toxic to the cells and can lead to cell death via an iron dependent cell death pathway called ferroptosis. However, cancer cells show remarkable resistance to iron induced cell death and grow normally under very high iron levels which is shown to be toxic for regular non cancerous cells. The mechanism of metabolic rewiring which renders protection to the cancer cells against iron toxicity remains unknown. Understanding the mechanism of iron toxicity and pathways to provide protection against this toxicity is therapeutic interested in developing novel treatment options. We show that colorectal cancer cells can withstand millimolar levels of iron without showing any growth defect whereas non cancerous cells cannot. We further identified that heme biosynthesis plays an important role in protecting CRC cells against iron. CRC cells show increased production of heme in response to increased intracellular iron. Furthermore inhibition of Amino levulinic acid dehydratase (ALAD), an enzyme involved in heme biosynthesis via a competitive inhibitor called Succinyl Acetone, makes the CRC cells highly sensitive to iron, suggesting that heme is required for iron buffering. Adding back heme to these cells reverse the iron sensitivity induced by inhibition of heme biosynthesis. Heme is an important iron containing molecule that plays various roles in regulating cellular metabolism along with systemic delivery of oxygen. Several heme-containing proteins are involved in ATP generation, redox balance, overall transcription and translation regulators etc. The future directions will include understanding the role of heme in regulating iron homeostasis and therefore toxicity mediated by iron. Furthermore, we will test the utility of heme inhibition in animal models of CRC in reducing the tumor burden.
