RRM2 elicits the metastatic potential of breast cancer cells by regulating cell invasion, migration and VEGF expression via the PI3K/AKT signaling

Abstract

Breast cancer is the second leading primary cause for cancer-related mortality among women and metastasis to the brain is a disastrous event for patients with increasing incidence. A previous study confirmed the critical function of RRM2 in breast cancer cell growth. Unfortunately, the role and fundamental molecular mechanism of RRM2 in breast cancer metastasis remains elusive. In the current study, higher RRM2 expression was validated in breast cancer tissues, especially in the brain metastasis group. Simultaneously, the expression of RRM2 was increased in breast cancer cells relative to the normal breast epithelial cell line MCF-10A, concomitant with higher levels of RRM2 in the highly metastatic MDA-MB-231 cell line relative to the weakly metastatic MCF-7 cell line. Knockdown of RRM2 by small interfering-RRM2 transfection notably suppressed the malignant metastatic behavior of breast cancer cells, including invasion and migration. Simultaneously, RRM2 downregulation also restrained the transcription and release of vascular endothelial growth factor (VEGF) in breast cancer cells. Moreover, inhibition of RRM2 dampened the activation of phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling by decreasing phosphorylated-AKT and downstream matrix metalloproteinases-2 expression.Intriguingly, reactivation of the PI3K/AKT pathway with its agonist insulin-like growth factor-1 reversed the adverse effects of RRM2 suppression on cancer cell invasion, migration and VEGF expression. Together, these findings suggest that RRM2 may act as a pro-metastatic factor to facilitate breast cancer metastasis by evoking cell invasion, migration and VEGF expression through the PI3K/AKT signaling pathway. This study may provide an attractive target for metastatic intervention in breast cancer.Key words: breast cancer, brain metastasis, RRM2, cell invasion and migration, vascular endothelial growth factor, phosphatidyl inositol 3 kinase/protein kinase B

RRM2 is a target for synthetic lethal interactions with replication stress checkpoint addiction in high-risk neuroblastoma

“…Deregulated expression, prognostic value as well as therapeutic exploitation of RRM2 has been reported in various types of cancer over the past decade including prostate cancer [11,12], glioblastoma [13], colorectal cancer [14], melanoma [15], Ewing sarcoma [10], cervical [16] and breast cancer [17,18]. Besides the finding of RRM2 as part of a four-gene prognostic signature in high-risk neuroblastoma and a recent report with limited data showing that siRNA mediated knockdown in SH-SY5Y cells caused a cell cycle arrest concomitant with apoptosis induction [19], the functional role of RRM2 in neuroblastoma tumorigenesis has remained unexplored thus far.…”

Multi-Omic Approaches to Breast Cancer Metabolic Phenotyping: Applications in Diagnosis, Prognosis, and the Development of Novel Treatments

“…Putluri et al observed that inhibiting RRM2 in BC cells significantly decreased proliferation and the expression of cell cycle genes and sensitized cells to tamoxifen treatment [65]. In agreement with the potential relevance of RRM2, additional studies have reported a reduction in proliferation [85,126] and tamoxifen resistance [158] in BC cell lines following RRM2 inhibition. Furthermore, associations between RRM2 overexpression and deterioration in BC survival have been widely reported, strongly suggesting a role as a targeted therapy for BC [61,120,121].…”

“…The authors observed a significant correlation between poor survival of BC patients and changes to the expression of RRM2 and adenosine monophosphate deaminase 1 (AMPD1), a key enzyme in de novo purine synthesis. These enzymes have been postulated as promising therapeutic targets in different tumor types, including BC [65,85,[123][124][125][126].…”

Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma

“…However, RRM2 is closely associated with sensitivity to Adriamycin. Inhibition of pancreatic cancer cell lines by co-administration of Adriamycin and RRM2 siRNA was four times higher than that provided by Adriamycin administration alone ( 41 ).RRM2 overexpression upregulates VEGF in oral and pancreatic cancers and promotes tumor angiogenesis through the PI3K/AKT signaling pathway ( 42 , 43 ). Certain TKIs may benefit patients with liposarcoma.…”