Research ArticleExperimental Studies
Open Access

Methionine Restriction, Not Cysteine Restriction, Is a Cancer-specific Vulnerability

YUTA MIYASHI, KOHEI MIZUTA, YOHEI ASANO, BYUNG MO KANG, JIN SOO KIM, QINGHONG HAN, SHUKUAN LI, MICHAEL BOUVET, YASUNORI TOME, KOTARO NISHIDA and ROBERT M. HOFFMAN
Anticancer Research January 2026, 46 (1) 135-141; DOI: https://doi.org/10.21873/anticanres.17929

Abstract

Background/Aim: Recently, there have been numerous publications on the induction of ferroptosis by cysteine restriction in cancer cells. The present report aimed to determine whether cysteine restriction (CR) is a cancer-specific vulnerability in comparison with methionine restriction (MR), which is a known cancer-specific vulnerability.

Materials and Methods: Human cancer cell lines (HCT116 colon cancer, 143B osteosarcoma or HT1080 fibrosarcoma) and normal human fibroblasts (Hs27) were cultured in Dulbecco’s modified Eagle’s medium (DMEM) with dialyzed fetal bovine serum from which methionine or cysteine or both or neither had been depleted. Cancer and normal cells were co-cultured in 12-well plates under the above conditions. HCT116 cells expressing green fluorescent protein, and 143B and HT1080 cells expressing red fluorescent protein, were visualized by fluorescence microscopy. Normal fibroblasts and cancer cells were visualized by phase-contrast microscopy as well.

Results: In co-culture, of either 143B, HCT116 or HT1080 with Hs27 human fibrosarcoma, CR was toxic to Hs27 normal fibroblasts as well as to all three cancer cell lines. In contrast, MR was toxic only to the cancer cells but not normal fibroblasts. Dual CR and MR was toxic to normal and cancer cells.

Conclusion: For all three cancer cell lines, HCT116 colon cancer, HT1080 fibrosarcoma and 143B osteosarcoma, both MR and CR were highly inhibitory in the co-cultures with Hs27 normal fibroblasts. In all cases MR had only a slight effect on normal fibroblasts, but CR was highly toxic to normal fibroblasts. Thus, MR is a cancer-specific vulnerability in contrast to CR which is toxic to both normal and cancer cells and is not a cancer-specificity vulnerability. Therefore, attempting to induce ferroptosis of cancer cells by CR does not appear to have potential as an effective cancer therapy.

Keywords:

Introduction

Recently, there have been many reports on the induction of ferroptosis in cancer cells by cysteine restriction (CR) (1-4). These reports suggest that induction of ferroptosis is a strategy for cancer therapy. Since 1959, it has been known that methionine restriction (MR) is a cancer-specific vulnerability which we know now is due to the methionine addiction of cancer cells, known as the Hoffman effect (5-10). The Hoffman effect of methionine addiction is stronger than the Warburg effect of glucose addiction as shown by comparison of methionine- and glucose-based positron-emission tomography (PET) images of patients with cancer (11). The present report compares the effects of CR and MR on cancer cells and normal cells in co-culture to determine if CR is a cancer specific vulnerability as is MR.

Materials and Methods

Cell culture. The HCT-116 human colon-cancer cell line, HT1080 human fibrosarcoma cell line, 143B human osteosarcoma cell line, and Hs27 normal human fibroblasts were obtained from the American Type Culture Collection (Manassas, VA, USA). Green fluorescent protein-expressing HCT116 cells, and red fluorescent protein-expressing 143B and HT1080 cells were established as described elsewhere (12-14). The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin (ThermoFisher Scientific, Waltham, MA, USA) in an incubator at 37°C with 5% CO2.

Co-culture. Each cancer cell line (5.0×104 cells) was seeded in 12-well plates together with Hs27 normal fibroblasts (5.0×104 cells). The day after seeding, after washing with phosphate-buffered saline (PBS), the medium in each well was replaced as follows: Complete medium [100 μM L-methionine and 150 μM L-cystine (300 μM cysteine), Thermo Fisher Scientific]. MR medium was without methionine, CR medium was without cysteine, and MR+CR medium was without methionine and cysteine. These media were prepared using methionine-, cysteine-, and glutamine-free DMEM, containing 10% dialyzed fetal bovine serum, 1% penicillin/streptomycin (ThermoFisher Scientific), supplemented with methionine and cysteine, as indicated above, and 4 mM glutamine.

Imaging. Four days after the medium was replaced, the wells were washed with PBS twice. Phase-contrast microscopic and fluorescence images (for green or red fluorescent protein) were acquired with an Olympus IX71 microscope (Olympus corp., Tokyo, Japan).

Results

The question we wished to answer in the present study was whether cysteine depletion is a cancer-specific vulnerability. We determined whether cysteine is a metabolic vulnerability specific to cancer cells by comparing the cysteine requirement of cancer cells with that of normal cells in a co-culture system of cancer and normal cells. As a positive control the methionine dependence of cancer and normal cells was also determined in the co-culture system.

We first compared the cysteine and methionine requirements of HCT116 colon cancer cells and Hs27 normal fibroblasts (Figure 1). In the co-culture of HCT116 and Hs27 cells under standard conditions with normal amounts of methionine and cysteine, the growth of the cancer cells was extensive and overtook the culture with respect to the normal cells (Figure 1A). Under conditions of methionine restriction (MR) in the presence of cysteine, cancer cells lost their viability while normal cells remained viable and proliferative (Figure 1B). In the presence of methionine but absence of cysteine (CR), both normal cells and cancer cells lost their viability (Figure 1C). In the absence of both methionine and cysteine (MR and CR), both normal cells and cancer cells lost their viability (Figure 1D).

Figure 1.
Figure 1.

Co-culture of HCT116 colon-cancer cells expressing green fluorescent protein with normal Hs27 fibroblasts under methionine or cysteine restriction as seen at day 4 using phase-contrast (left) and fluorescence (right) microscopy. (A) Control co-culture of cells in Dulbecco’s modified Eagle’s medium (DMEM) containing both methionine and cysteine. (B) Co-culture of cells in methionine-restricted DMEM in the presence of cysteine. (C) Co-culture of cells in cysteine-restricted DMEM in the presence of methionine. (D) Co-culture of cells in methionine- and cysteine-restricted DMEM. For each set of phase-contrast and fluorescence images, the views are of the same microscopic field. All images were acquired at 100× magnification. Please see Materials and Methods for details.

We next compared the cysteine and methionine requirements of HT1080 fibrosarcoma cells and Hs27 normal fibroblasts (Figure 2). In the co-culture of HT1080 and Hs27 cells under standard conditions with normal amounts of methionine and cysteine, cancer-cell growth overtook the culture with respect to the normal cells (Figure 2A). Under conditions of MR in the presence of cysteine, cancer cells lost their viability while normal cells remained viable and proliferative (Figure 2B). In the presence of methionine but CR, both normal cells and cancer cells lost their viability (Figure 2C). Under MR and CR, both normal cells and cancer cells lost their viability (Figure 2D).

Figure 2.
Figure 2.

Co-culture of HT1080 fibrosarcoma cells expressing red fluorescent protein with Hs27 normal fibroblasts under methionine or cysteine restriction as seen at day 4 using phase-contrast (left) and fluorescence (right) microscopy. (A) Control co-culture of cells in Dulbecco’s modified Eagle’s medium (DMEM) containing both methionine and cysteine. (B) Co-culture of cells in methionine-restricted DMEM in the presence of cysteine. (C) Co-culture of cells in cysteine-restricted DMEM in the presence of methionine. (D) Co-culture of cells in methionine- and cysteine-restricted DMEM. For each set of phase-contrast and fluorescence images, the views are of the same microscopic field. All images were acquired at 100× magnification. Please see Materials and Methods for details.

We next compared the cysteine and methionine requirements of 143B osteosarcoma cells and Hs27 normal fibroblasts (Figure 3). In the co-culture of 143B and Hs27 cells under standard conditions with normal amounts of methionine and cysteine, cancer cell growth overtook the culture with respect to normal cells (Figure 3A). Under conditions of MR in the presence of cysteine, cancer cells lost their viability while normal cells remained viable and proliferative (Figure 3B). In the presence of methionine but CR, both normal cells and cancer cells lost their viability (Figure 3C). Under MR and CR, both normal cells and cancer cells lost their viability (Figure 3D).

Figure 3.
Figure 3.

Co-culture of 143B osteosarcoma cells expressing red fluorescent protein with Hs27 fibroblasts under methionine or cysteine restriction as seen at day 4 using phase-contrast (left) and fluorescence (right) microscopy. (A) Control co-culture of cells in Dulbecco’s modified Eagle’s medium (DMEM) containing both methionine and cysteine. (B) Co-culture of cells in methionine-restricted DMEM in the presence of cysteine. (C) Co-culture of cells in the cysteine-restricted DMEM in the presence of methionine. (D) Co-culture of cells in methionine- and cysteine-restricted DMEM. For each set of phase-contrast and fluorescence images, the views are of the same microscopic field. All images were acquired at 100× magnification. Please see Materials and Methods for details.

Thus, cysteine restriction is not a cancer-specific vulnerability. It affects both normal cells and cancer cells extensively, causing both to lose their viability. In contrast, methionine restriction specifically affects the cancer cells, with little effect on normal cells.

Discussion

In the present study, for all three cancer cell lines tested, both MR and CR were highly inhibitory of cancer-cell viability. MR had a slight effect on normal fibroblasts, whereas CR was also highly toxic to normal fibroblasts. Additionally, these results were consistent for both carcinoma (HCT-116) and sarcoma cells (HT1080 and 143B). Thus, MR is a cancer-specific vulnerability, as known since 1959 (5), while CR is toxic to both normal and cancer cells. In our co-culture model, the present results, which are consistent with the Hoffman effect of methionine addiction specifically of cancer cells, were determined visually and simply. Therefore, attempts to induce ferroptosis in cancer cells by CR do not seem to have potential as an effective cancer therapy. Methionine restriction is effective because it targets the fundamental hallmark of cancer, methionine addiction (5-44). Methionine restriction is showing clinical promise (45-48).

A limitation of the present study is that it was in vitro. However, the co-culture system is internally controlled with cancer and normal cells in the same culture well (34,41). Future studies will use in vivo models.

Acknowledgements

This paper is dedicated to the memory of A.R. Moossa, MD; Professor Philip Miles; Sun Lee, MD; Richard W. Erbe, MD; Professor Milton Plesur; Professor Gordon H. Sato; Professor Li Jiaxi; Masaki Kitajima, MD; Shigeo Yagi, Ph.D.; Jack Geller, MD; Joseph R Bertino, MD; J.A.R. Mead, Ph.D.; Eugene P. Frenkel, MD; John Mendelsohn, MD; Professor I.J. Fidler; Professor Lev Bergelson; Professor Sheldon Penman; Professor John R. Raper; Professor J.D. Watson; and Joseph Leighton, MD. The Robert M. Hoffman Foundation for Cancer Research provided funds for the present study.

Footnotes

  • Authors’ Contributions

    YM and RMH designed the study. YM wrote the manuscript. RMH revised the manuscript. KM, YA, BMK, JSK, QH, SL, BM, YT and KN critically reviewed the manuscript. YM performed the experiments. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no competing interests in relation to this study.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received September 22, 2025.
  • Revision received October 22, 2025.
  • Accepted October 30, 2025.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Methionine Restriction, Not Cysteine Restriction, Is a Cancer-specific Vulnerability
YUTA MIYASHI, KOHEI MIZUTA, YOHEI ASANO, BYUNG MO KANG, JIN SOO KIM, QINGHONG HAN, SHUKUAN LI, MICHAEL BOUVET, YASUNORI TOME, KOTARO NISHIDA, ROBERT M. HOFFMAN
Anticancer Research Jan 2026, 46 (1) 135-141; DOI: 10.21873/anticanres.17929
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