Balancing redox stress: anchorage-independent growth requires reductive carboxylation

Clint.A Stalnecker, Ahmad.A Cluntun, Richard.A Cerione


The ability of a cell to exhibit anchorage independent growth is a hallmark of cancer, and has been extensively investigated in hopes of finding new therapeutic strategies. In particular, the processes that give rise to and support this dysregulated growth phenotype, which allows cells to proliferate in the absence of survival signals resulting from their attachment to a basement membrane, has been of interest. The contribution of oncogenes and tumor suppressors on anchorage independent growth has been well studied; however, the alterations in cellular metabolism that support this process are much less defined. Changes in cellular metabolism are among the most notable hallmarks of solid tumors, where glucose is imported at high rates and exported from cancer cells as lactate, instead of being utilized within the citric acid cycle (TCA cycle) (1,2). This process, known as the Warburg effect, represents the primary metabolic phenotype associated with cancer cells. In order to adapt to this altered metabolism, cancer cells have been shown to rely on other primary metabolic pathways to support their increased requirements for biosynthesis and redox control to allow for their sustained proliferation. In particular, glutamine metabolism has been shown to supplement the decrease in glucose-derived carbon entering the TCA cycle in 2D cultured cancer cells (Figure 1, compare quiescent versus proliferating cells). However, it remains unclear how expendable glutaminkfueled anaplerosis is for cells grown in 3D. In their recent Nature article, DeBerardinis and coworkers [2016] set out to describe the metabolic alterations that accompany the anchorage-independent growth of human cancer cells when cultured as a 2D monolayer or as a 3D spheroid, thereby mimicking the detachment from the extracellular matrix that often occurs during tumorigenesis (3). They find that the same cancer cells exhibit drastically different metabolic phenotypes when grown as spheroids than they do in a monolayer culture.