Abstract
Cancer stem cell (CSC) is a challenge in the therapy of triple-negative breast cancer (TNBC). Intratumoral hypoxia is a common feature of solid tumor. Hypoxia may contribute to the maintenance of CSC, resulting in a poor efficacy of traditional treatment and recurrence of TNBC cases. However, the underlying molecular mechanism involved in hypoxia-induced CSC stemness maintenance remains unclear. Here, we report that hypoxia stimulated DNA double-strand breaks independent of ATM kinase activation (called oxidized ATM in this paper) play a crucial role in TNBC mammosphere formation and stemness maintenance by governing a specific energy metabolism reprogramming (EMR). Oxidized ATM up-regulates GLUT1, PKM2, and PDHa expressions to enhance the uptake of glucose and production of pyruvate rather than lactate products, which facilitates glycolytic flux to mitochondrial pyruvate and citrate, thus resulting in accumulation of cytoplasmic acetyl-CoA instead of the tricarboxylic acid (TCA) cycle by regulating ATP-citrate lyase (ACLY) activity. Our findings unravel a novel model of TNBC-CSC glucose metabolism and its functional role in maintenance of hypoxic TNBC-CSC stemness. This work may help us to develop new therapeutic strategies for TNBC treatment.
Highlights
Triple-negative breast cancer (TNBC) is a breast cancer subtype as defined by the lack of estrogen receptor (ER) and progesterone receptor (PR), as well as human epidermal growth factor receptor-2 (HER-2) expressions
An increasing evidence suggests that some intermediates in energy metabolism regulate epigenetic and transcriptional changes associated with stemness maintenance and self-renewal, including S-adenosyl methionine (SAM) produced via the onecarbon cycle, acetyl-CoA (Ac-CoA) from glycolysis, α-ketoglutarate and flavin adenine dinucleotide (FAD) from the tricarboxylic acid (TCA) cycle, and NAD+
It has been demonstrated that hypoxia in breast tumors is linked to poor patient survival rate and recurrence, and Cancer stem cell (CSC) may play a crucial role in tumor recurrence[15]
Summary
Triple-negative breast cancer (TNBC) is a breast cancer subtype as defined by the lack of estrogen receptor (ER) and progesterone receptor (PR), as well as human epidermal growth factor receptor-2 (HER-2) expressions. TNBC predominantly presents as invasive ductal carcinomas, characterized by poor differentiation, high proliferative capacity, a large overall tumor size[2], and increased lymph node involvement at the time of diagnosis, Over the years, stem cell metabolism was viewed as an accessory substance of cell fate status rather than a critical regulatory agent. An increasing evidence suggests that some intermediates in energy metabolism regulate epigenetic and transcriptional changes associated with stemness maintenance and self-renewal, including S-adenosyl methionine (SAM) produced via the onecarbon cycle, acetyl-CoA (Ac-CoA) from glycolysis, α-ketoglutarate (αKG) and flavin adenine dinucleotide (FAD) from the tricarboxylic acid (TCA) cycle, and NAD+. Official journal of the Cell Death Differentiation Association. Yang et al Cell Death and Disease (2020)11:508 from the integration of glycolysis and OXPHOS6,7. In the mammalian cells cytosol, ATP-citrate lyase (ACLY) cleaves glucose-derived citrate to nuclear acetyl-
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