Alphavbeta3 integrin blocking inhibits apoptosis and induces autophagy in murine breast tumor cells

Author(s)

Bressani Lino, Rafael Luis ^[1] ; dos Santos, Patty Karina ^[1] ; Deriggi Pisani, Graziele Fernanda ^[1] ; Altei, Wanessa Fernanda ^[1] ; Cominetti, Marcia Regina ^[2] ; Selistre-de-Araujo, Heloisa Sobreiro ^[1]

Affiliation

^[1] Univ Fed Sao Carlos, Dept Physiol Sci, Ctr Biol & Hlth Sci, Rd Washington Luis, Km 235-SP-310, BR-13565905 Sao Carlos, SP - Brazil

^[2] Univ Fed Sao Carlos, Dept Gerontol, Ctr Biol & Hlth Sci, Rd Washington Luis, Km 235-SP-310, BR-13565905 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH; v. 1866, n. 12 DEC 2019.
• Web of Science Citations: 0

Abstract

Integrins are cell receptors that mediate adhesion to the extracellular matrix (ECM) and regulate cell migration, a crucial process in tumor invasion. The alpha(v)beta(3) integrin recognizes the arginine-glycine-aspartic acid (RGD) motif in ECM proteins and it can be antagonized by RGD-peptides, resulting in decreased cell migration and invasion. RGD-based drugs have shown disappointing results in clinical trials; however, the reasons for their lack of activity are still obscure. Aiming to contribute to a better understanding of the molecular consequences of integrin inhibition, we tested a recombinant RGD-disintegrin (DisBa-01) in two types of murine cell lines, breast tumor 4T1BM2 cells and L929 fibroblasts. Only tumor cells showed decreased motility and adhesion, as well as morphologic alterations upon DisBa-01 treatment (100 and 1000 nM). This result was attributed to the higher levels of alpha(v)beta(3) integrin in 4T1BM2 cells compared to L929 fibroblasts making the former more sensitive to DisBa-01 blocking. DisBa-01 induced cell cycle arrest at the S phase in 4T1BM2 cells, but it did not induce apoptosis, which was consistent with the decrease in caspase-3, 8 and 9 expression at mRNA and protein levels. DisBa-01 increases PI3K, Beclin-1 and LC3B expression in tumor cells, indicators of autophagic induction. In conclusion, alpha(v)beta(3) integrin blocking by DisBa-01 results in inhibition of adhesion and migration and in the activation of an autophagy program, allowing prolonged survival and avoiding immediate apoptotic death. These observations suggest new insights into the effects of RGD-based inhibitors considering their importance in drug development for human health. (AU)

• FAPESP's process: 13/00798-2 - The extracellular matrix in aging, exercise and in the tumor microenvironment
• Grantee: Heloisa Sobreiro Selistre de Araújo
• Support Opportunities: Research Projects - Thematic Grants