No abstract

The rapid development of metastatic lesions remains the leading cause of mortality for patients with osteosarcoma. CD155 serves a key role in cancer cell migration, invasion and metastasis. However, the function and mechanism of CD155 has not been explored in osteosarcoma metastasis. In the present study, we found that CD155 was significantly upregulated in lung metastatic tissue and the highly metastatic cell line K7M2-WT (K7M2) of osteosarcoma. Overexpression of CD155 in K7M2 cells enhanced lung metastasis, while inhibition of CD155 by an anti-CD155 monoclonal antibody reduced metastasis. Blocking of CD155 also decreased migration and invasion of K7M2 cells . A western blot analysis revealed that blocking of CD155 inhibits metastasis by downregulating focal adhesion kinase (FAK) and phosphorylated FAK (pFAK) in osteosarcoma. The results revealed that CD155 serves a crucial role in the metastasis of osteosarcoma by regulating FAK and may provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma.

We here showed that ADCK1 (AarF domain-containing kinase 1), a mitochondrial protein, is upregulated in human osteosarcoma (OS) tissues and OS cells. In primary and established OS cells, ADCK1 shRNA or CRISPR/Cas9-induced ADCK1 knockout (KO) remarkably inhibited cell viability, proliferation and migration, and provoked apoptosis activation. Conversely, ectopic ADCK1 overexpression exerted pro-cancerous activity by promoting OS cell proliferation and migration. ADCK1 depletion disrupted mitochondrial functions in OS cells and induced mitochondrial membrane potential reduction, ATP depletion, reactive oxygen species production. Significantly, ADCK1 silencing augmented doxorubicin-induced apoptosis in primary OS cells. mTOR activation is important for ADCK1 expression in OS cells. The mTOR inhibitors, rapamycin and AZD2014, as well as mTOR shRNA, potently decreased ADCK1 expression in primary OS cells. In nude mice, the growth of subcutaneous pOS-1 xenografts was largely inhibited when bearing ADCK1 shRNA or ADCK1 KO construct. Moreover, ADCK1 KO largely inhibited pOS-1 xenograft in situ growth in proximal tibia of nude mice. ADCK1 depletion, apoptosis activation and ATP reduction were detected in pOS-1 xenografts bearing ADCK1 shRNA or ADCK1 KO construct. Together, the mitochondrial protein ADCK1 is required for OS cell growth and is a novel therapeutic target of OS.

Data have increasingly shown that interlukin-24 (IL-24) has growth suppression activity and can induce apoptosis in a broad spectrum of tumor cells. However, the therapeutic effect of IL-24 on human neuroblastoma has rarely been explored. In this study, we used a human neuroblastoma cell line (SH-SY5Y) to reveal the effect of adenovirus-mediated IL-24 (Ad-IL24) gene therapy for neuroblastoma. We showed that Ad-IL24 effectively inhibited the proliferation of SH-SY5Y cells in vitro by conspicuously inducing apoptosis. To further explore the molecular mechanism by which Ad-IL24 induced apoptosis in SH-SY5Y tumor cells, we found that Ad-IL24 increased the expression of Bax and promoted the activation of caspase-3, while decreasing Bcl-2 levels. We also demonstrated that Ad-IL24 significantly inhibited tumor growth in vivo in a xenograft neuroblastoma tumor in athymic nude mice. In summary, Ad-IL24 overexpression exerted potent antitumor activity via inducing apoptosis in neuroblastoma cells. Therefore, IL-24 has the potential to serve as an agent for gene therapy in the treatment of neuroblastoma.

ZD55-shMYCN provides a novel agent for treating MYCN-amplified and p53-inactive aggressive neuroblastoma, representing a promising approach for further clinical development.