Ribonucleotide reductase small subunit M2B (RRM2B) plays an essential role in maintaining mitochondrial homeostasis.
Mitochondrial permeability transition pore (MPTP) is a key regulator of mitochondrial homeostasis.
MPTP contributes to cell death and is crucial in
cancer progression. RRM2B's relation to
MPTP is not well known, and the role of RRM2B in
cancer progression is controversial. Here, our aim was to study the role of RRM2B in regulating
MPTP and the association between RRM2B and clinicopathological manifestations in
breast cancer. Analysis of Rrm2b-/- mice cells found changes consistent with
MPTP opening, including mitochondrial swelling and upregulation of
cyclophilin D (CypD), a
protein that activates
MPTP opening. Silencing of RRM2B gene expression in MCF7 and KB cell lines led to
MPTP opening. Accordingly, dysfunctional oxidative phosphorylation and elevated
superoxide levels were also detected in RRM2B-silenced MCF7 and KB cell lines, which was consistent with the findings by gene set enrichment analysis of 159
breast cancer cases that genes involving respiratory electron transport were enriched in high-RRM2B
breast cancer, and genes involving biologic oxidation were enriched in low-RRM2B breast
cancers. A metabolomic study revealed that
spermine levels in RRM2B-silenced MCF7 and KB cells were only 5% and 8% of control levels, respectively. Addition of exogenous
spermine to RRM2B-silenced MCF7 and KB cells was able to reverse the
MPTP opening induced by RRM2B deficiency. These results suggest that RRM2B may induce
MPTP opening through reducing
spermine levels. Immunohistochemical analysis of 148
breast cancer cases showed that RRM2B and CypD
protein levels were inversely correlated in
breast cancer specimens (P<0.05), so were their associated clinicopathologic parameters that high-level RRM2B expression was associated with better clinicopathological features. We conclude that RRM2B deficiency leads to
MPTP opening mediated by
spermine. Coupling of low RRM2B and high CypD expression is associated with aggressive manifestations of
breast cancer.