Abstract
Neuroblastoma (NB) is an aggressive, relapse-prone infancy tumor of the sympathetic nervous system and is the leading cause of death among preschool age diseases, so the search for novel therapeutic targets is crucial. Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development, and in the DNA damage response, of various human cancers. Golgi dispersal is a common feature of DNA damage response in mammalian cells. Understanding how cells react to DNA damage is essential in order to recognize the systems used to escape from elimination. We induced DNA damage in two human neuroblastoma cell lines by curcumin. The exposure of neuroblastoma cells to curcumin induced: (a) up-regulation of GOLPH3+ cells; (b) augmentation of double-strand breaks; (c) Golgi fragmentation and dispersal throughout the cytoplasm; (d) increase of apoptosis and autophagy; (e) increased expression of TPX2 oncoprotein, able to repair DNA damage. Primary neuroblastoma samples analysis confirmed these observations. Our findings suggest that GOLPH3 expression levels may represent a clinical marker of neuroblastoma patients’ responsiveness to DNA damaging therapies—and of possible resistance to them. Novel molecules able to interfere with GOLPH3 and TPX2 pathways may have therapeutic benefits when used in combination with standard DNA damaging therapeutic agents in neuroblastoma
Highlights
Neuroblastoma (NB), the most common extra-cranial solid cancer in children, originates from the precursors of the sympathetic nervous system [1]
We show the linkage between DNA damage and Golgi phosphoprotein 3 (GOLPH3) expression in NB, and how this can cause cell resistance even through higher levels of TPX2 oncogene expression
Since TPX2 plays a principal function in the DNA damage response pathway and co-localizes with γ-H2AX at chromosomal double strand breakage sites [38,39], we analyzed the expression of TPX2 on the same cells and we found an opposite trend: TPX2 was activated by curcumin treatment but it resulted up-regulated when the cells recovered from that treatment started growing again, indicating a proliferation comparable to control cells (Figure 3A, 4B)
Summary
Neuroblastoma (NB), the most common extra-cranial solid cancer in children, originates from the precursors of the sympathetic nervous system [1]. The clinical courses of the disease are deeply heterogeneous: half of the tumors regresses spontaneously or after short therapies, while the other half is lethal in the majority of patients despite multiple stronger treatments. A number of patients are deceased due to the resistance to chemotherapeutic drugs. To prolong the survival of patients affected by NB, it is crucial to determine the mechanism underlying the occurrence of drug resistance and find an effective treatment method to increase drug sensitivity. Tumor cells can further enhance their drug resistance by exploiting autophagy mechanisms, a lysosomal degradation pathway responsible for the withdrawal of aged organelles and proteins [16]. Previous studies have indicated that therapeutic agents can induce autophagy, so facilitating cancer cell survival during drug-induced metabolic stress [16]
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