Abstract
Glioblastoma multiforme is the most common malignant brain tumor in adults, with an average survival of less than one year due to its resistance to therapy. Recent studies reported that GBM initiates from CD133-expressing cancer stem cells (CSC). However, the efficacy of CSC targeting is limited. A newly developed approach in cancer treatment is the forced differentiation of cancer cells. Here, we show that the treatment of the novel small molecule, CG500354, into CD133-expressing human primary GBM cells induces growth arrest by cell cycle regulators, p53, p21, p27 and phase-specific cyclins, and neural differentiation, as confirmed by neural progenitor/precursor markers, nestin, GFAP and Tuj1. When GBM-derived cells caused the tumors in NOD/SCID mice, CG500354 induced GBM-derived cells differentiation into Tuj1 and GFAP expressing cells. We next demonstrated that CG500354 plays a tumor-suppressive role via cAMP/CREB signaling pathway. CG500354 increases not only the extracellular cAMP level but also the protein level of PKA and CREB. Additionally, both mimetic substances, Forskolin and Rolipram, revealed comparable results with CG500354. Our findings indicate that induction of growth arrest and neural differentiation via cAMP/CREB signaling pathway by CG500354 treatment suggests the novel targeting of PDE4D in the development of new drugs for brain tumor therapy.
Highlights
Glioblastoma multiforme is the most common malignant brain tumor in adults, with an average survival of less than one year due to its resistance to therapy
We show that the treatment of the novel small molecule, CG500354, into CD133-expressing human primary GBM cells induces growth arrest by cell cycle regulators, p53, p21, p27 and phase-specific cyclins, and neural differentiation, as confirmed by neural progenitor/precursor markers, nestin, GFAP and Tuj[1]
Our findings indicate that induction of growth arrest and neural differentiation via cAMP/cAMP response element-binding protein (CREB) signaling pathway by CG500354 treatment suggests the novel targeting of phosphodiesterase 4D (PDE4D) in the development of new drugs for brain tumor therapy
Summary
Glioblastoma multiforme is the most common malignant brain tumor in adults, with an average survival of less than one year due to its resistance to therapy. Recent studies reported that GBM initiates from CD133-expressing cancer stem cells (CSC). Our findings indicate that induction of growth arrest and neural differentiation via cAMP/CREB signaling pathway by CG500354 treatment suggests the novel targeting of PDE4D in the development of new drugs for brain tumor therapy. Regarding the biological properties of CSCs, recent evidence has emerged that CSCs are similar to tissue-specific stem cells with respect to self-renewal and multi-lineage differentiation capacity, but they differ in their long-term proliferative potential This uncontrolled renewal potential of CSCs might be the reason for tumor relapse after conventional cancer therapy. Piccirillo and colleagues have demonstrated that bone morphogenetic protein 4 (BMP4) induces the neural differentiation of www.nature.com/scientificreports human GBM-derived cells They showed that BMP4 exerts growth inhibitory effects on CD133-expressing GBM-derived cells in vitro and that BMP4 treatment hinders tumorigenicity in vivo[17]. Recent reports have indicated the significant role of cAMP/CREB signaling pathway in the differentiation of cancer cells, the cellular mechanism by which cAMP and CREB force the differentiation process remains to be unveiled
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