Abstract
The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR/IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC.
Highlights
Discoidin domain receptor 1 (DDR1) is a tyrosine-kinase receptor activated by fibrillar collagen type I and collagens type II, III, IV, and V [1,2]
To investigate whether DDR1 affected insulin-like growth factor signaling (IIGFs)-driven metabolic reprogramming, we used human breast cancer (BC) cells MCF7 stably transfected with an myc-tagged IGF2 vector
We have previously shown that MCF7/IGF2 cells are characterized by constitutive activation of both the IGF1 receptor (IGF1R) and the isoform A (IR-A), phosphorylation of key downstream signaling molecules such as AKT and ERK1/2, and increased metabolic activity sustained by high aerobic glycolysis and high oxidative phosphorylation (OxPhos) [8]
Summary
Discoidin domain receptor 1 (DDR1) is a tyrosine-kinase receptor activated by fibrillar collagen type I and collagens type II, III, IV, and V [1,2]. DDR1 plays a complex role in development and organogenesis as well as in inflammation and fibrosis [3,4,5]. DDR1 is often dysregulated in cancer, and it has been implicated in various aspects of cancer progression, including cell proliferation and invasion, promotion of stem phenotype, metastasis, and modulation of chemotherapy response [6,7]. We have recently described a feed-forward loop between DDR1 and the insulin/insulin-like growth factor signaling (IIGFs) [8]. DDR1 preferentially modulated the expression of the oncofetal IR isoform IR-A by altering the balance of IR isoforms
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