Chronic nickel (II) exposure induces the stemness properties of cancer cells through repressing isocitrate dehydrogenase (IDH1)

Abstract

Background: Nickel is a component of biomedical alloys that is released during corrosion or friction and causes cytotoxicity, mutation, differentiation or even carcinogenesis in tissues. However, the mechanisms underlying the potential hazards of Nickel-containing alloys implanted in the human body by surgery remain uncertain.

Objective: To study the effect of Ni(II) (NiCl_2•6H₂O) on cancer cells.

Methods: A549 and RKO cells were treated with various concentrations of Ni(II) to determine the effect of Ni(II) on cellular viability using a CCK8 assay. Flow cytometry was performed to analyze the effect of Ni(II) on apoptosis and the cell cycle. Sphere-forming assays were conducted to examine the stemness properties of A549 and RKO cells. Western blotting was to evaluate the expression levels of SOX2, IDH1, HIF-1ɑ and β-catenin. The expression of isocitrate dehydrogenase (IDH1) in rectum adenocarcinoma (READ) was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). Kaplan-Meier analysis was used to calculate the correlation between survival and IDH1 expression.

Results: Long-term exposure (120 days) to 100 µM Ni(II) significantly repressed cell proliferation, decreased colony formation and arrested the cell cycle at the G₀/G₁ phase. In addition, the stem-like traits of A549 and RKO cells were significantly augmented. Ni(II) also significantly decreased the protein expression of IDH1 and the synthesis rate of NAPDH, which competitively inhibited α-ketoglutarate (α-KG) generation. The downregulation of IDH1 not only promoted β-catenin accumulation in the cell nucleus in a HIF-1ɑ signaling-dependent manner but also induced the expression of the transcription factor SOX2 to maintain the stemness properties of cancer cells. Moreover, IDH1 expression negatively correlated with the clinicopathologic characteristics of READ.

Conclusion: These findings demonstrate that chronic and continuous release of Ni(II) to the microenvironment suppresses IDH1 expression and augments the stemness properties of cancer cells via the activation HIF-1ɑ/β-catenin/SOX2 pathway to enhance local tumor recurrence in patients with implanted Nickel-containing alloys at surgical sites.

Keywords: Chronic Ni(II) exposure; Isocitrate dehydrogenase (IDH1); Nickel-containing alloys; Stemness properties of cancer cells.