RESUMO
BACKGROUND: 14,15-epoxyeicosatrienoic acid (14,15-EET) is an important lipid signaling molecule involved in the regulation of tumor metastasis, however, the role and molecular mechanisms of 14,15-EET activity in breast cancer cell epithelial-mesenchymal transition (EMT) and drug resistance remain enigmatic. METHODS: The 14, 15-EET level in serum and in tumor or non-cancerous tissue from breast cancer patients was measured by ELISA. qRT-PCR and western blot analyses were used to examine expression of integrin αvß3. The role of 14, 15-EET in breast cancer cell adhesion, invasion was explored by adhesion and Transwell assays. The role of 14, 15-EET in breast cancer cell cisplatin resistance in vitro was determined by MTT assay. Western blot was conducted to detect the protein expressions of EMT-related markers and FAK/PI3K/AKT signaling. Xenograft models in nude mice were established to explore the roles of 14, 15-EET in breast cancer cells EMT and cisplatin resistance in vivo. RESULTS: In the present study, we show that serum level of 14, 15-EET increases in breast cancer patients and 14, 15-EET level of tumor tissue is higher than that of non-cancerous tissue. Moreover, 14, 15-EET increases integrin αvß3 expression, leading to FAK activation. 14, 15-EET induces breast cancer cell EMT via integrin αvß3 and FAK/PI3K/AKT cascade activation in vitro. Furthermore, we find that 14, 15-EET induces breast cancer cells EMT and cisplatin resistance in vivo, αvß3 integrin and the resulting FAK/PI3K/AKT signaling pathway are responsible for 14, 15-EET induced-breast cancer cells cisplatin resistance. CONCLUSIONS: Our findings suggest that inhibition of 14, 15-EET or inactivation of integrin αvß3/FAK/PI3K/AKT pathway could serve as a novel approach to reverse EMT and cisplatin resistance in breast cancer cells.
Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cisplatino/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Integrina alfaVbeta3/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido 8,11,14-Eicosatrienoico/farmacologia , Animais , Neoplasias da Mama/genética , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Fosforilação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Conditioned place avoidance (CPA) paradigm has been used to investigate the affective component of pain. Although the anterior cingulate cortex (ACC) has been demonstrated to play an important role in the affective aspect of pain, whether the other prefrontal subdivisions are involved in pain-related aversion is unknown. The present study investigated the role of the prelimbic cortex (PL) and infralimbic cortex (IL) in the acquisition and expression of formalin-induced CPA (F-CPA) in rats. GABAA receptor agonist muscimol was bilaterally microinjected into PL/IL before or after the formalin-paired training, to explore the effect of temporary inactivation of PL/IL on the acquisition and expression of F-CPA, respectively. The results showed that inactivation of PL rather than IL impaired the acquisition and expression of F-CPA. Moreover, the PL inactivation did not block the acquisition of LiCl-induced CPA, suggesting that PL may be specifically implicated in the pain-emotion related encoding. These results indicate that PL but not IL is involved in the aversive dimension of pain.
