Oncotarget

Research Papers:

Inactivation of beta1 integrin induces proteasomal degradation of Myc oncoproteins

Manabu Sasada, Takuya Iyoda, Tatsufumi Asayama, Yusuke Suenaga, Shunsuke Sakai, Naoya Kase, Hiroaki Kodama, Sana Yokoi, Yoichiro Isohama and Fumio Fukai _

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Oncotarget. 2019; 10:4960-4972. https://doi.org/10.18632/oncotarget.27131

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Abstract

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

Correspondence to:

Fumio Fukai,email: fukai@rs.noda.tus.ac.jp

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

ABSTRACT

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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