Magnesium ions induce senescence-like state via `ATM/CHK2/p21` pathway, inhibiting cervical cancer growth in vitro and in vivo.

Cervical cancer remains a significant global health burden, often limited by insufficient tumor targeting, severe systemic toxicity, and drug resistance with conventional treatments. Inducing cellular senescence, a stable cell cycle arrest, offers a promising therapeutic strategy to halt cancer progression. While Mg2+ is crucial for genome stability and cell cycle regulation, its specific anti-tumor mechanism, particularly through senescence induction, has been largely unexplored. This study investigates whether Mg2+ can impede cervical cancer by triggering a senescence-like phenotype via the ATM/CHK2/p21 signaling pathway, addressing a critical gap in understanding its therapeutic potential.

Researchers investigated the anti-cancer effects of Mg2+ using HeLa cells in vitro and a BALB/c nude mouse xenograft model in vivo. In vitro, cell proliferation, migration, and invasion were assessed using CCK-8, EdU, wound-healing, and Transwell assays. Senescence-related markers and pathway protein expression were examined via SA-β-gal staining and western blotting. Cells were treated with varying concentrations of Mg2+, with 20 mM Mg2+ being a key concentration for senescence induction. An ATM inhibitor was used to confirm pathway involvement. In vivo, tumor growth and safety were evaluated following intratumoral Mg2+ injection, monitoring body weight, liver/kidney function, and serum magnesium levels.

Mg2+ significantly inhibited proliferation, migration, and invasion of HeLa cells in a concentration-dependent manner. Treatment with 20 mM Mg2+ markedly increased SA-β-gal positivity and decreased Lamin B1 expression, confirming the induction of a senescence-like state. This effect was accompanied by the activation of the ATM/CHK2/p21 pathway; importantly, the upregulation of p21 was reversed by an ATM inhibitor, demonstrating pathway specificity. ELISA results showed that 10 mM Mg2+ enhanced IL-6 and TNF-α secretion, indicating an effective induction of the senescence-associated secretory phenotype (SASP). Higher concentrations, however, diminished this SASP effect, potentially due to reduced cell viability. In vivo experiments in a BALB/c nude mouse xenograft model demonstrated that intratumoral Mg2+ inhibited tumor growth without notable alterations in body weight, liver and kidney function, or serum magnesium levels, suggesting a favorable safety profile. > The localized high concentration of magnesium ions induces cells to enter a senescence-like state via the ATM/CHK2/p21 pathway, thereby selectively suppressing malignant cellular behaviors.