Intramitochondrial Src kinase links mitochondrial dysfunctions and aggressiveness of breast cancer cells

Abstract

High levels and activity of Src kinase are common among breast cancer subtypes, and several inhibitors of the kinase are currently tested in clinical trials. Alterations in mitochondrial activity is also observed among the different types of breast cancer. Src kinase is localized in several subcellular compartments, including mitochondria where it targets several proteins to modulate the activity of the organelle. Although the subcellular localization of other oncogenes modulates the potency of known treatments, nothing is known about the specific role of intra-mitochondrial Src (mtSrc) in breast cancer. The aim of this work was to determine whether mtSrc kinase has specific impact on breast cancer cells. We first observed that activity of mtSrc is higher in breast cancer cells of the triple negative subtype. Over-expression of Src specifically targeted to mitochondria reduced mtDNA levels, mitochondrial membrane potential and cellular respiration. These alterations of mitochondrial functions led to lower cellular viability, shorter cell cycle and increased invasive capacity. Proteomic analyses revealed that mtSrc targets the mitochondrial single-stranded DNA-binding protein, a regulator of mtDNA replication. Our findings suggest that mtSrc promotes aggressiveness of breast cancer cells via phosphorylation of mitochondrial single-stranded DNA-binding protein leading to reduced mtDNA levels and mitochondrial activity. This study highlights the importance of considering the subcellular localization of Src kinase in the development of potent therapy for breast cancer.

SRC Kinase in Glioblastoma: News from an Old Acquaintance

“…Noteworthily, it has been demonstrated that SRC can affect glycolysis in cancer cells through a direct phosphorylation of pyruvate dehydrogenase (PDH), inhibiting its activity and driving the Warburg effect [ 87 ]. These evidences, on the one hand, highlighted the role of SRC in driving metabolic reprogramming and, on the other hand, clearly support SRC mitochondrial localization, as previously observed [ 88 , 89 , 90 , 91 ].…”

Nanomedicine of tyrosine kinase inhibitors

“…In CML, fusion of chromosome 22 and 9 gives rise to chimeric Bcr-Abl protein, where Abl kinase domain is constitutively activated and drives the disease progression 35 . Src kinase was found to be overexpressed in liver 36 and breast cancer 37 , which had mitigating effect on mitochondrial activity, and consequently supported tumor progression and metastasis. MET and HER2 gene amplifications are considered important driver oncogene alterations in lung adenocarcinomas 38 .…”

Nuclear Functions of the Tyrosine Kinase Src

“…In their cytoplasmic functions, SFKs can interact with integrins, actins, GTPase-activating proteins, scaffold proteins such as p130CAS and paxillin, and kinases such as focal adhesion kinases, thereby affecting cell adhesion and migration [1]. Beside these membrane/cytoplasmic functions, SFKs have been described in other subcellular compartments, as the nucleus, the Golgi apparatus, late endosomes/lysosomes and mitochondria [24][25][26][27][28]. Subcellular distribution of SFKs other than Src are reported in the Table 1.…”