SRC Family Kinase Inhibition in Ewing Sarcoma Cells Induces p38 MAP Kinase-Mediated Cytotoxicity and Reduces Cell Migration

Abstract

Ewing sarcoma (ES) is a highly aggressive bone and soft tissue cancer, representing the second most common primary malignant bone tumor in children and adolescents. Although the development of a multimodal therapy, including both local control (surgery and/or radiation) and systemic multidrug chemotherapy, has determined a significant improvement in survival, patients with metastatic and recurrent disease still face a poor prognosis. Moreover, considering that ES primarily affects young patients, there are concerns about long-term adverse effects of the therapy. Therefore, more rational strategies, targeting specific molecular alterations underlying ES, are required. Recent studies suggest that SRC family kinases (SFKs), which are aberrantly activated in most cancer types, could represent key therapeutic targets also for ES. Here, we challenged ES cell lines with a recently developed selective SFK inhibitor (a pyrazolo[3,4-d]pyrimidine derivative, called SI221), which was previously shown to be a valuable proapoptotic agent in other tumor types while not affecting normal cells. We observed that SI221 significantly reduced ES cell viability and proved to be more effective than the well-known SFK inhibitor PP2. SI221 was able to induce apoptosis in ES cells and also reduced ES cell clonogenic potential. Furthermore, SI221 was also able to reduce ES cell migration. At the molecular level, our data suggest that SFK inhibition through SI221 could reduce ES cell viability at least in part by hindering an SFK-NOTCH1 receptor-p38 mitogen-activated protein kinase (MAPK) axis. Overall, our study suggests a potential application of specific SFK inhibition in ES therapy. J. Cell. Physiol. 232: 129-135, 2017. © 2016 Wiley Periodicals, Inc.

A biosystems approach to identify the molecular signaling mechanisms of TMEM30A during tumor migration

“…SRC is a proto-oncogene that is aberrantly activated in most types of cancer [29], which is consistent with our results showing that SRC is significantly increased in both cell types. Further, the FAK-SRC signaling pathway regulates the invasion of lung cancer [30] and Ewing sarcoma cells [29], indicating that SRC may be a key therapeutic target for cancer treatment.…”

“…SRC is a proto-oncogene that is aberrantly activated in most types of cancer [29], which is consistent with our results showing that SRC is significantly increased in both cell types. Further, the FAK-SRC signaling pathway regulates the invasion of lung cancer [30] and Ewing sarcoma cells [29], indicating that SRC may be a key therapeutic target for cancer treatment. It is widely accepted that all modes of migration require RHO GTPase, including RHO and CDC42 (Fig 4A and 4B) due to its effects on the regulation of actin dynamics that plays a critical role in cell migration depending on the environment [31, 32].…”

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

“…For example, dasatinib is believed to affect YAP/TAZ primarily through targeting SRC [251]. Studies in both osteosarcoma and Ewing sarcoma cell lines reported inhibition of the migration and induction of apoptosis by dasatinib [252,253].…”

The Natural cAMP Elevating Compound Forskolin in Cancer Therapy: Is It Time?

“…Moreover, the cAMP signaling interacts with other intracellular signaling pathways, including cytokine and Ras‐Raf‐ Erk pathways (Follin‐Arbelet et al, ; Spina et al, ; Tai et al, ; Cheng et al, ; Park and Juhnn, ). Notably, these signaling connections also play an important role in cancer biology and a combined blockade of such signaling pathways is considered a relevant strategy for therapeutic intervention to fight cancer (Awada and Aftimos, ; Indovina et al, ; Kidger and Keyse, ).…”