Targeting PINK1 and MQC in brain tumors

Glioblastoma multiforme (GBM) is one of the most common brain tumors with very poor prognosis, and one of the most lethal tumors due to its highly invasive nature, high recurrence, and resistance to multimodal cancer therapy. GBM contains small subpopulations of cancer therapy-resistant tumor-initiating cells (also referred to as cancer-stem cells; CSCs) that share functional properties, such as self-renewal and capability of multi-lineage differentiation, with normal neural stem cells (NSCs). CSCs are believed to play a central role in the initiation and development of various tumors, as well as the recurrence of malignant tumors after conventional therapy. The identification of CSCs in various tumors has opened exciting new therapeutic opportunities. However, the molecular pathways maintaining the stem cell-like properties and tumorigenic behavior of the CSCs are poorly defined. Cancer cells are known to undergo active glycolysis even in the presence of sufficient oxygen, which would promote more efficient energy production through mitochondrial oxidative phosphorylation (OXPHOS). This phenomenon was referred to as the Warburg effect. Although it was initially assumed that cancer cells are defective in OXPHOS, later studies have found that some cancer cells, including CSCs, are more active in OXPHOS than normal cells. Further, OXPHOS has been exploited for cancer treatment. Very little is known about the regulation and function of OXPHOS in CSCs. The Notch signaling pathway plays a critical role in cell fate determination in NSCs and CSCs. Aberrant Notch activation is found in a wide range of tumors, including leukemia, breast cancer, and GBM. Notch mediates short-range cell-to-cell communication through interaction with ligands presented by neighboring cells. Notch consists of a ligand-binding extracellular domain, a transmembrane domain, and an intracellular domain (NICD) with transcriptional activity. In canonical Notch signaling, ligand-receptor interaction leads to sequential proteolytic cleavages and the translocation of cleaved NICD to the nucleus, where it regulates Notch-dependent transcription through interacting with transcription factor(s). Although the canonical Notch signaling pathway and its core components have been heavily studied, Notch can also act non-canonically to exert its biological effects by interacting with cytoplasmic components. Here, we discuss the emerging mechanisms and roles of non-canonical Notch signaling in preserving NSCs and CSCs through regulation of mitochondrial function. Drosophila neuroblasts (NBs) offer an excellent model for recapitulating key aspects of stem cell biology underpinning stem cell maintenance and brain tumorigenesis. NBs are similar to mammalian NSCs in lineage hierarchy, including the presence of transit-amplifying intermediate progenitors (IPs). Inhibition …