Increased Heme Synthesis in Ovarian Cancer and Triple Negative Breast Cancer Cells Leads to Downregulation of Glycolysis, Mitochondrial Respiration, and Cell Migration.

Abstract

Cancer cells undergo a complex rearrangement of metabolic pathways involved in biosynthetic processes to support tumor initiation and progression. Targeting glycolysis and TCA cycle that provide precursors for biosynthetic pathways emerged as a potential therapeutic strategy in some cancers. Heme has a potential to regulate both glycolysis and TCA cycle. Heme serves as a prosthetic group in proteins and enzymes that sense, transport, or use oxygen, such as hemoglobin, myoglobin, cytochrome complexes, catalases, and cyclooxygenases. Heme is also required for ATP production by the mitochondrial electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). The first and rate‐limiting step in heme synthesis is production of 5‐aminolevulinic acid (ALA). In this study, we show that promoting heme synthesis by ALA supplementation in ovarian cancer and triple negative breast cancer cells leads to downregulation of glycolysis and lactate production, mitochondrial respiration, as well as cell migration. The mechanism responsible for reduced glycolysis and cell migration involves destabilization of heme‐regulated transcription factor Bach1. Support or Funding Information Supported by NIH GM120710

Divergent iron-regulatory states contribute to heterogeneity in breast cancer aggressiveness

“…HO-1 KD increased cellular heme levels and abrogated collective invasion in HD Col1, which aligns with other studies showing that increasing heme levels decreases TNBC cell migration (86). Likewise, several recent reports suggest that elevated heme synthesis underlies enhanced OXPHOS and tumorigenicity in TNBC, ovarian cancer, and non-small cell lung cancer, and pancreatic cancer (59, 87, 88). Our functional studies suggest that ACO1/IRP1, MRCK, and OXPHOS could be targets of interest for TNBC cells in this state, motivating future studies in vivo .…”