Methionine Dependence of Cancer

Abstract

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed.

Keywords: S-adenosylmethionine; SAM-checkpoint; cancer; cell cycle; methionine.

Figure 1

The Hoffman Effect. Non-tumorigenic cell lines have the same proliferation rate in media containing methionine or media where methionine is replaced with the immediate metabolic precursor homocysteine. However, most cancer cells cannot proliferate in homocysteine medium, and induce cell cycle arrest followed by apoptosis when cultured under these conditions. Cancer cells readily synthesize methionine from homocysteine, but appear to depend on exogenously supplied methionine. This cancer-specific metabolic dependence is referred to as the methionine dependence of cancer, the methionine stress sensitivity of cancer, or simply the Hoffman effect.

Figure 2

Methionine metabolism. (A) Metabolic connections between the methionine cycle, which produces methylation potential, the methionine salvage pathway, which recycles methionine from byproducts of the polyamine synthesis pathway, and the transsulfuration pathway, which generates cysteine and glutathione to combat oxidation. (B) The remethylation step of homocysteine as part of the methionine cycle and synthesis of S-adenosylmethionine (SAM).

Figure 3

Possible connection between the Warburg and Hoffman effects. Glycolysis is connected to the methionine cycle through the folate cycle, whereby serine derived from 3-phosphoglycerate provides one-carbon units. This pathway is important in cancer cells because the folate cycle feeds both nucleotide and SAM biosynthesis. SAM levels are especially impacted by the folate cycle because it is important for re-methylation of homocysteine to methionine, as well as ATP synthesis. Both methionine and ATP are substrates for formation of SAM.

Figure 4

The SAM cell cycle checkpoint. Yeast cells and mammalian cells arrest the cell cycle when SAM levels are limited. This arrest can be induced in yeast and mammalian cells by either SAM limitation or methionine depletion, and in cancer cells also by a shift to homocysteine medium (Hoffman effect). Cells show a robust arrest in the G1 phase of the cell cycle due to lack of stable pre-replication complexes to initiate S-phase. A delay in G2/M is also observed. In cancer cell lines S/G2 arrest has also been reported when cells were cultured in homocysteine medium.

Figure 5

SAM-checkpoint in yeast and mammals. In yeast SAM levels are sensed by the ubiquitin ligase SCF^Met30, which ubiquitylates several substrates including the transcription factor Met4 to coordinate methionine metabolism with cell cycle control. What senses SAM abundance in mammalian cells in the context of cell proliferation is currently unknown. Both yeast and mammalian cells induce the SAM-checkpoint arrest by destabilizing pre-replication complexes. What components signal SAM levels to pre-replication complex stability is not well understood, but p38, MK2, and activating phosphorylation of T160 of Cdk2 have been implicated.