Dormant cancer cells that survive anti-cancer therapy can lead to cancer recurrence and disseminated metastases that prove fatal in most cases.Recently, specific dormant polyploid giant cancer cells (PGCC) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as demonstrated by previous clinical data. In this study, we report the biological properties of PGCC, including mitochondrial alterations, and reveal that autophagy is a critical mechanism of PGCC induction.Moreover, pharmacological or genetic inhibition of autophagy greatly impaired PGCC formation, significantly suppressing metastasis and improving survival in a mouse model. Mechanistically, chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Analysis of the transcriptional and epigenetic landscape of PGCC revealed overexpression of RIPK1, and the scaffolding function of RIPK1 was required for AMPK-mTOR pathway-induced PGCC survival. High numbers of PGCCs correlated with shorter recurrence time and worse survival outcomes in NPC patients. Collectively, these findings suggest a therapeutic approach of targeting dormant PGCCs in cancer.
SignificanceResearch.
Cyclin-dependent kinase-5 (CDK5), a serine/threonine kinase which can be activated by its neuron-specific activator p35, or its truncated form p25, plays an important role in a variety of neuronal events, including neuronal migration, synaptic transmission, and neuronal death. Accumulating evidence has shown that abnormal activation of CDK5 was a critical neuronal pro-death signal in central nervous system (CNS) diseases. However, it remains unclear how CDK5 functions upon neuronal apoptosis following intracerebral hemorrhage (ICH). In the present study, we established ICH models by injecting autologous whole blood into the right basal ganglia of adult rats and assessed their neurological deficits by behavioral tests. CDK5 protein levels and kinase activities were upregulated adjacent to the hematoma following ICH. Immunofluorescent staining showed CDK5 was mainly localized in neurons, rather than in astrocytes or oligodendrocytes. Furthermore, active caspase-3, an apoptotic marker, showed a temporally parallel expression with the protein levels/kinase activities of CDK5 following ICH. Meantime, myocyte enhancer factor 2D (MEF2D), a pro-survival transcription factor which could be phosphorylated inactivation by CDK5, also exhibited high phosphorylation levels following ICH. In vitro, we obtained a consistent upregulation of CDK5 kinase activity in primary cortical neurons after thrombin treatment. Knocking down CDK5 kinase activity suppressed neuronal apoptosis and coupled with reduced MEF2D phosphorylation at ser(444) residues. Thus, we speculated that CDK5 might exert an important function in the regulation of neuronal apoptosis following ICH.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.