L-Methionine inhibits growth of human pancreatic cancer cells.

We have previously shown that L-methionine inhibits proliferation of breast, prostate, and colon cancer cells. This study extends these findings to BXPC-3 (mutated p53) and HPAC (wild-type p53) pancreatic cancer cells and explores the reversibility of these effects. Cells were exposed to L-methionine (5 mg/ml) for 7 days or for 3 days, followed by 4 days of culture without L-methionine (recovery). Cell proliferation, apoptosis, and cell cycle effects were assessed by flow cytometry after staining for Ki-67 or annexin V/propidium iodide. Cell proliferation was reduced by 31-35% after 7 days of methionine exposure; the effect persisted in BXPC-3 and HPAC cells after 4 days of recovery. Methionine increased apoptosis by 40-75% in HPAC cells, but not in BXPC-3 cells. Continuous exposure to methionine caused accumulation of BXPC-3 cells in the S phase and HPAC cells in both the G0/G1 and S phases; however, after 4 days of recovery, these effects disappeared. In conclusion, L-methionine inhibits proliferation and interferes with the cell cycle of BXPC-3 and HPAC pancreatic cancer cells; the effects on apoptosis remarkably persisted after methionine withdrawal. Apoptosis was induced only in BXPC-3 cells. Some of the differences in the effects of methionine between cell lines may be related to disparate p53 status. These findings warrant further studies on the potential therapeutic benefit of L-methionine against pancreatic cancer.

l-Methionine may modulate the assembly of SARS-CoV-2 by interfering with the mechanism of RNA polymerase.

Coronaviruses have received worldwide attention following several severe acute respiratory syndrome (SARS) epidemics. In 2019, the first case of coronavirus disease (COVID-19) caused by a novel coronavirus (SARS-coronavirus 2 [CoV-2]) was reported. SARS-CoV-2 employs RNA-dependent RNA polymerase (RdRp) for genome replication and gene transcription. Recent studies have identified a sulfur (S) metal-binding site in the zinc center structures of the RdRp complex. This metal-binding site is essential for the proper functioning of the viral helicase. We hypothesize that the use of essential nutrients can permeabilize the cell membranes. The oxidation of the metal-binding site occurs via analogs of the essential S-containing amino acid, l-Methionine. l-Methionine can operate as a carrier, and its binding would cause the potential disassembly of RdRp via the S complex and drive methyl donors via a possible countercurrent exchange mechanism and electrical-chemical gradient leading to SARS-CoV-2 replication failure. Our previously published hypothesis on the control of cancer cell proliferation suggests that the presence of a novel disulfide/methyl- adenosine triphosphate pump as an energy source would allow this process. The S binding site in l-Methionine serves as a potential target cofactor for SARS-CoV RdRp, thus providing a possible avenue for the future development of vaccines and antiviral therapeutic strategies to combat COVID-19.

L-methionine-induced alterations in molecular signatures in MCF-7 and LNCaP cancer cells.

BACKGROUND: Methionine inhibits proliferation of breast and prostate cancer cells. Here, we determined the influence of L-methionine on functional molecular signatures in these cell lines. METHODS: MCF-7 and LNCaP cells were treated with L-methionine (5 mg/ml) for 72 h. Changes in molecular signatures of these cells were examined by microarray analysis of 15,814 probes in triplicate experiments. RESULTS: In LNCaP cells, 325 genes were up-regulated by methionine, and 517 genes down-regulated. In MCF-7 cells, 86 genes were up-regulated and 135 genes down-regulated. Ninety-eight genes were regulated in the same direction by methionine in both cells lines, and five other genes were changed in expression in opposite directions. CONCLUSION: Several of the up-regulated genes encode proteins involved in cellular redox regulation, suggesting that methionine may enhance antioxidant mechanisms. Many of the down-regulated genes belong to protein kinase families that may be related to the anti-proliferative effects of methionine on breast and prostate cancer cells.

Suppression by L-methionine of cell cycle progression in LNCaP and MCF-7 cells but not benign cells.

BACKGROUND/AIM: Methionine inhibits proliferation of breast and prostate cancer cells. This study aimed to determine cell cycle effects of methionine and selectivity for cancer cells. MATERIALS AND METHODS: MCF-7 (breast), LNCaP (prostate), and LS-174 (colon) cancer cells (wild-type p53), DU-145 (prostate) and SW480 (colon) cancer cells (mutated p53), and immortalized, non-tumorigenic MCF-10A (breast), BPH-1 (prostate), and NCM-460 (colon) epithelial cells were used. Cell cycle effects were assessed by flow cytometry and cell cycle-related gene expression by microarray analysis and QRT-PCR. RESULTS: L-Methionine at 5 mg/ml for 72 hours (non-apoptotic) arrested cell cycle in LNCaP, DU145, and MCF-7 cells, but not in untransformed cells, nor in LS-174 cells. LNCaP and MCF-7 cells were arrested at G(1), but DU-145 at S. Methionine up-regulated CDKIs and down-regulated CDKs. CONCLUSION: L-Methionine selectively inhibits proliferation of breast and prostate cancer cells, but not non-tumorigenic cells, and may thus have therapeutic benefits. p53 status appeared to determine the cell cycle stage at which methionine acts.

Methionine inhibits cellular growth dependent on the p53 status of cells.

BACKGROUND: Methionine, an essential amino acid, is important for normal growth and development, as it is required for both protein and polyamine synthesis as well as in methylation reactions. It has been reported that high concentrations of methionine inhibit cellular growth and gene expression in the human breast tumor-derived MCF-7 cells. These effects are thought to be mediated by the modulation of p53. However, the generalizability of this observation and the precise role of p53 in methionine-induced growth suppression needs to be determined. METHODS: To determine if the inhibition of cell growth by methionine applies to other cell lines and to characterize further the role of p53 in methionine-induced growth suppression, we have assessed the effects of methionine on cellular growth and proliferation and p53 expression in cells expressing native p53, eg, breast cancer MCF-7 cells and prostate cancer LNCaP cells, and also in cells expressing a mutated (point) form of p53, eg, prostate cancer DU-145 cells. These cell lines were treated with varying concentrations of L-methionine. The effects of L-methionine on cell growth were assayed by using cell viability assays and immunostaining for Ki-67, a cell proliferation marker. The effects of methionine on p53 expression were assessed by using reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blot analysis. The role of p53 in L-methionine-mediated growth suppression was evaluated using short-interference RNA for p53 (siRNA-p53), immunoprecipitation, and direct DNA sequencing. RESULTS: We demonstrated that methionine at a concentration of 1 to 5 mg/mL inhibited the growth of both MCF-7 and LNCaP cells. In association with the inhibition of growth, methionine also inhibited native p53 expression at the mRNA and protein levels, respectively. Furthermore, transfection with siRNA-p53, to knock down p53 expression, increased cell growth and proliferation of the LNCaP cells even when they were exposed to methionine. In contrast, the same treatment did not diminish growth or proliferation of the DU-145 cells. Also, the expression of mutated p53 at the mRNA or protein levels was not altered. CONCLUSION: Our results extend a prior observation to other cell lines and demonstrate that high concentrations of methionine suppress the expression of native but not mutated p53. These inhibitory effects on cellular growth are, in part, due to inhibition of cellular proliferation probably via a p53-dependent pathway.