Inactivation of beta1 integrin induces proteasomal degradation of Myc oncoproteins
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Manabu Sasada1,2,3,4, Takuya Iyoda1,5, Tatsufumi Asayama1, Yusuke Suenaga4, Shunsuke Sakai1, Naoya Kase1, Hiroaki Kodama6, Sana Yokoi4, Yoichiro Isohama2,3 and Fumio Fukai1,2
1 Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
2 Translational Research Center, Research Institute of Science and Technology, Tokyo University of Science, Chiba, Japan
3 Laboratory of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
4 Cancer Genome Center, Chiba Cancer Center Research Institute, Chiba City, Chiba, Japan
5 Department of Pharmacy, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda City, Yamaguchi, Japan
6 Faculty of Science and Engineering, Saga University, Saga, Japan
|Fumio Fukai,||email:||[email protected]|
Keywords: integrin; Myc; proteasomal degradation; fibronectin; neuroblastoma
Abbreviations: ECM: extracellular matrix; Ab: antibody; mAb: monoclonal antibody; FN: fibronectin
Received: February 03, 2019 Accepted: July 15, 2019 Published: August 13, 2019
The MYC family oncogenes (MYC, MYCN, and MYCL) contribute to the genesis of many human cancers. Among them, amplification of the MYCN gene and over-expression of N-Myc protein are the most reliable risk factors in neuroblastoma patients. On the other hand, we previously found that a peptide derived from fibronectin, termed FNIII14, is capable of inducing functional inactivation in β1-integrins. Here, we demonstrate that inactivation of β1-integrin by FNIII14 induced proteasomal degradation in N-Myc of neuroblastoma cells with MYCN amplification. This N-Myc degradation by FNIII14 reduced the malignant properties, including the anchorage-independent proliferation and invasive migration, of neuroblastoma cells. An in vivo experiment using a mouse xenograft model showed that the administration of FNIII14 can inhibit tumor growth, and concomitantly a remarkable decrease in N-Myc levels in tumor tissues. Of note, the activation of proteasomal degradation based on β1-integrin inactivation is applicable to another Myc family oncoprotein, c-myc, which also reverses cancer-associated properties in pancreatic cancer cells. Collectively, β1-integrin inactivation could be a new chemotherapeutic strategy for cancers with highly expressed Myc. FNIII14, which is a unique pharmacological agent able to induce β1-integrin inactivation, may be a promising drug targeting Myc oncoproteins for cancer chemotherapy.
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