Osteopontin Knockdown Inhibits a_v,�₃Integrin-Induced Cell Migration and Invasion and Promotes Apoptosis of Breast Cancer Cells by Inducing Autophagy and Inactivating the PI3K/Akt/mTOR Pathway

Abstract

Background: Osteopontin (OPN) is associated with tumor formation, progression and metastasis, and increased OPN levels have been associated with poor survival in breast cancer. We investigated the mechanisms responsible for OPN activity, and the relationships between OPN expression and clinical parameters in breast cancer. Methods: OPN mRNA and protein levels were compared in malignant and benign breast tumors by polymerase chain reaction (PCR) and immunohistochemistry, respectively, and levels in breast cancer cells were determined by PCR and western blotting. The effects of lentiviral-mediated knockdown of OPN on OPN and α_v,β₃ integrin expression, cell invasion and migration, autophagy and apoptosis were analyzed in MDA-MB-231 cells. Results: OPN expression increased with aggressiveness of breast cancer phenotype. OPN knockdown inhibited α_v,β₃ integrin expression in MDA-MB-231 cells, with subsequent inhibition of cell migration and invasion. Knockdown also inhibited the PI3K/Akt/mTOR pathway, promoted expression of the autophagy-related gene products LC3 and Beclin 1, and increased apoptosis. OPN expression was positively associated with tumor grade and lymph node metastasis. Conclusion: These results suggest that knockdown of OPN may inhibit breast cancer metastasis by regulating α_v,β₃ integrin expression and inducing autophagy and subsequent inhibition of PI3K/Akt/mTOR signaling, thus providing further insights into the complex mechanisms regulating tumor growth and metastasis.

ß₃-Integrin Inhibits Lipopolysaccharide-Induced Autophagy in Cardiomyocytes via the Akt Signaling Pathway

“…Consistent with our finding, Zhang et al [30] observed that knocking down osteopontin, the main ligand of integrin, resulted in downregulation of β 3 -integrin and elevated the expression of LC3-II and Beclin-1 in MDA-MB-231 cells. Inhibiting the function of integrin causes decreased autophagosome formation in starved prostate epithelial cells [31].…”

Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells

“…The PI3K/Akt/mTOR signaling pathway promotes cellular growth, migration, protein synthesis, survival and metabolism in response to growth factors and nutrient availability (8). PI3K activates Akt, which leads to the phosphorylation of mTOR via a number of regulators (17).…”

“…For instance, B-cell lymphoma-2 (Bcl-2) can promote the proliferation of MCF-7 cells, an effect that is associated with the inhibition of autophagy (7). In addition, a previous study demonstrated that inhibition of the phosphoinositide 3-kinase (PI3K)/RAC-α serine-threonine-protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway inhibits MDA-MB-231 cell proliferation, and that the PI3K/Akt/mTOR cascade is a key signaling pathway that regulates autophagy (8).…”

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

“…mTOR is suggested to promote fibrogenesis through promotion of proliferation and trans-differentiation of HSCs into myo fibroblast-like cells [44]. Also, recent studies linked mTOR to the signaling pathway of the α V β 3 integrin, a receptor for vitronectin, which is the primary molecule required for fibroblast attachment and spreading [45]. Another possible mechanism that promotes liver fibrosis progression is the development of hepatic steatosis [46].…”