Inactivation of beta1 integrin induces proteasomal degradation of Myc oncoproteins

• Published in: Oncotarget Vol. 10; no. 48; pp. 4960 - 4972
• Main Authors: Sasada, Manabu, Iyoda, Takuya, Asayama, Tatsufumi, Suenaga, Yusuke, Sakai, Shunsuke, Kase, Naoya, Kodama, Hiroaki, Yokoi, Sana, Isohama, Yoichiro, Fukai, Fumio
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 13.08.2019
• Subjects: Research Paper; neuroblastoma; fibronectin; integrin; proteasomal degradation; Myc
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.27131

The family oncogenes ( , , and ) contribute to the genesis of many human cancers. Among them, amplification of the 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 amplification. This N-Myc degradation by FNIII14 reduced the malignant properties, including the anchorage-independent proliferation and invasive migration, of neuroblastoma cells. An 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.