Nestin regulates proliferation and invasion of gastrointestinal stromal tumor cells by altering mitochondrial dynamics

Abstract

Nestin is widely expressed in numerous tumors and has become a diagnostic and prognostic indicator. However, the exact mechanism by which nestin contributes to tumor malignancy remains poorly understood. Here, we found marked upregulation of nestin expression in highly proliferative and invasive gastrointestinal stromal tumor (GIST) specimens. Nestin knockdown in GIST cells reduced the proliferative and invasive activity owing to a decrease of mitochondrial intracellular reactive oxygen species (ROS) generation. Furthermore, nestin was co-localized with mitochondria, and knockdown of nestin increased mitochondrial elongation and influenced the mitochondrial function, including oxygen consumption rates, ATP generation and mitochondrial membrane potential and so on. In exploring the underlying mechanism, we demonstrated nestin knockdown inhibited the mitochondrial recruitment of Dynamin-related protein1 and induced the change of mitochondrial dynamics. Thus, nestin may have an important role in GIST malignancy by regulating mitochondrial dynamics and altering intracellular ROS levels. The findings provide new clues to reveal mechanisms by which nestin mediates the proliferation and invasion of GISTs.

A neuronal network of mitochondrial dynamics regulates metastasis

“…Mitochondrial dynamics has recently emerged as a driver of malignancy10, contributing to oncogene-directed transformation26, tumour progression27 and cell invasion28. Using a novel algorithm that tracks quantitative changes in mitochondrial morphology, we have shown here that loss of SNPH heightened both fusion and fission events in tumour cells, consistent with modulation of key effectors of organelle dynamics, including increased expression of MFN1 and recruitment of Drp1 to mitochondria10.…”

Nuclear Nestin deficiency drives tumor senescence via lamin A/C-dependent nuclear deformation

“…Moreover, Li et al 17 found that Nestin cooperates with Hedgehog (Hh) signaling to drive medulloblastomas growth through blocking the Hh pathway transcription factor-Gli3 phosphorylation and its subsequent proteolytic processing. Recently, our study demonstrated that Nestin can also regulate proliferation and invasion of gastrointestinal stromal tumor cells by recruiting dynamin-related protein1 to alter mitochondrial dynamics 13 , indicating Nestin may not only participate in processing signal transduction, motility, and cellular stress but also play a role in regulating spatial localization of cell organelles.…”

“…In adult tissues, most Nestin-positive cells are found in areas of stem/progenitor populations, like hair follicle 3 – 5 , skeletal muscle satellite cells 6 , testis 7 , kidney 8 , and bone marrow 9 , where they might be engaged in active proliferation, tissue regeneration, and wound healing 10 . In addition, Nestin can play a role in pathogenesis and it is expressed in several types of malignancies, including glioma 11 , melanoma 12 , gastrointestinal tumors 13 , prostate cancer 14 , and so on. Furthermore, higher levels of Nestin expression seems to correlate with greater malignancy and poorer prognosis 11 – 15 .…”

Preventing BRCA1/ZBRK1 repressor complex binding to the GOT2 promoter results in accelerated aspartate biosynthesis and promotion of cell proliferation

“…The abundance of aspartate and a-KG were normalized to the cell number. For mitochondrial aspartate, a-KG and NADH/NAD + redox detection, mitochondria were separated from 5 9 10 6 transfected cells or MEF-BRCA1 M/M and MEF-BRCA1 +/+ cells via commercial kits (Beyotime, Shanghai, China), which has been reported to separate mitochondria from cytosol (Wang et al, 2016a). The mitochondria were homogenized in PBS and the supernatant was collected.…”