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Inactivation of beta1 integrin induces proteasomal degradation of Myc oncoproteins.


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 ?1-integrins. Here, we demonstrate that inactivation of ?1-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 ?1-integrin inactivation is applicable to another Myc family oncoprotein, c-myc, which also reverses cancer-associated properties in pancreatic cancer cells. Collectively, ?1-integrin inactivation could be a new chemotherapeutic strategy for cancers with highly expressed Myc. FNIII14, which is a unique pharmacological agent able to induce ?1-integrin inactivation, may be a promising drug targeting Myc oncoproteins for cancer chemotherapy.

SUBMITTER: Sasada M 

PROVIDER: S-EPMC6697639 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Inactivation of beta1 integrin induces proteasomal degradation of Myc oncoproteins.

Sasada Manabu M   Iyoda Takuya T   Asayama Tatsufumi T   Suenaga Yusuke Y   Sakai Shunsuke S   Kase Naoya N   Kodama Hiroaki H   Yokoi Sana S   Isohama Yoichiro Y   Fukai Fumio F  

Oncotarget 20190813 48


The <i>MYC</i> family oncogenes (<i>MYC</i>, <i>MYCN</i>, and <i>MYCL</i>) contribute to the genesis of many human cancers. Among them, amplification of the <i>MYCN</i> 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 in  ...[more]

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