Extracellular pressure stimulates adhesion of sarcoma cells via activation of focal adhesion kinase and Akt

Abstract

Summary Pressure increases sarcoma cell adhesiveness via intracellular activation of Akt and FAK. Perioperative manipulation or forces in lymphatic or circulatory systems may potentiate local recurrence or distant metastasis. Background The effect of extracellular pressure on adhesion and adhesiogenic focal adhesion kinase (FAK) and Akt signaling in sarcomas was investigated. Methods Human sarcoma cells (HT-1080 fibrosarcoma, KHOS-240S osteosarcoma, A-673 rhabdomyosarcoma) were subjected to increased pressure followed by adhesion assay. Two cell lines were pretreated with the FAK inhibitor 1,2,4,5-benzenetetraamine tetrahydrochloride (Y15) or Akt IV inhibitor, followed by Western analysis for activated FAK and Akt. Parallel studies were conducted in cells from a resected human fibrous histiosarcoma. Results Pressure increased adhesion in all three sarcoma lines and primary histosarcoma cells by 7–18% (n=6, p<0.01 each). Pressure activated FAK and Akt (n=5, p<0.01). Inhibiting FAK or Akt inhibited FAK or Akt phosphorylation and the stimulation of adhesion by increased pressure (n=5 each, p<0.01 each). Conclusion Pressure increases sarcoma cell adhesiveness via Akt and FAK. Perioperative manipulation or forces in lymphatic or circulatory systems may potentiate local recurrence or distant metastasis.

Inhibitory effects of indirubin‐3′‐monoxime against human osteosarcoma

“…Further investigations show that the survivin expression is associated with the cell cycle distribution, migration, invasion as well as the clinical staging, chemosensitivity, metastasis, recurrence, and prognosis . Similarly, as cytoplasmic nonreceptor protein tyrosine kinase, FAK is one of the key regulators in the cell adhesion and contact, which are essential in cell migration, invasion, and metastasis . Previous studies suggested that the inhibition of survivin or FAK decreased the OS cell proliferation, migration, and invasion significantly in vitro and in vivo .…”

“…[40][41][42] Similarly, as cytoplasmic nonreceptor protein tyrosine kinase, FAK is one of the key regulators in the cell adhesion and contact, which are essential in cell migration, invasion, and metastasis. 43,44 Previous studies suggested that the inhibition of survivin or FAK decreased the OS cell proliferation, migration, and invasion significantly in vitro and in vivo. 45 Our data showed I3M could reduce the expression of survivin and FAK, which contributed to its inhibitory effects on the OS cell proliferation, apoptosis, cell cycle, migration, and invasion.…”

Protein Kinase B/AKT and Focal Adhesion Kinase: Two Close Signaling Partners in Cancer

“…However, the overall pressureactivated pathway that involves FAK and AKT and mediates an increase in integrin-mediated binding affinity and cell adhesiveness in response to increased extracellular pressure has been demonstrated in a broad range of cancer cell types, including colon, breast, head and neck carcinoma, lymphoma, and sarcoma [102][103][104][105][106][107][108][109][110]. However, the overall pressureactivated pathway that involves FAK and AKT and mediates an increase in integrin-mediated binding affinity and cell adhesiveness in response to increased extracellular pressure has been demonstrated in a broad range of cancer cell types, including colon, breast, head and neck carcinoma, lymphoma, and sarcoma [102][103][104][105][106][107][108][109][110].…”

Targeting Focal Adhesion Kinase in Neuroblastoma

“…These investigators showed that inhibition of FAK with 1,2,4,5-benzenetetraamine tetrahydrochloride resulted in decreased breast cancer tumor growth [47] and pancreatic cancer tumor growth both in vitro and in nude mouse models [48]. In addition, a recent study by Perry showed that inhibition of FAK with 1,2,4,5-benzenetetraamine tetrahydrochloride resulted in decreased adhesion in the sarcoma cell lines HT-1080, KHOS-240S and A-673 [49]. In the neuroblastoma cell lines SK-N-AS and SK-N-BE(2) ( MYCN nonamplified and amplified, respectively), treatment with 1,2,4,5-benzenetetraamine tetrahydrochloride resulted in decreased cellular attachment and viability, and increased apoptosis in vitro as evaluated by trypan blue exclusion, Hoechst 33258 staining, and immunoblotting [50].…”