Anti-BECN1 polyclonal antibody

DDE (dichlorodiphenyldichloroethylene) is an environmental metabolite of the pesticide DDT, which is still present in the environment, and its insecticidal properties are used to fight malaria and the Zika virus disease. We showed for the first time that the neurotoxic effects of DDE involve autophagy, as demonstrated by elevated levels of Becn1, Map1lc3a/MAP1LC3A, Map1lc3b. and Nup62/NUP62 and an increase in autophagosome formation. The suggestion that the aryl hydrocarbon receptor (AHR) and the constitutive androstane receptor (CAR) are involved in the neurotoxic effect of DDE was supported by increases in the mRNA and protein expression of these receptors, as detected by gPCR. EUSA, immunofluorescence labeling and confocal microscopy. Selective antagonists of the receptors, including alpha-naphthoflavone, CH223191, and CINPA 1, inhibited p,p'-DDE- and o,p'-DDE-induced LDH release and caspase-3 activity, while specific siRNAs (Ahr and Car siRNA) reduced the levels of p,p'-DDE- and o,p'-DDE-induced autophagosome formation. Although the neurotoxic effects of DDE were isomer independent, the mechanisms of p,p'- and o,p'-DDE were isomer specific. Therefore, we identified previously unknown mechanisms of the neurotoxic actions of DDE that, in addition to inducing apoptosis, stimulate autophagy in mouse neocortical cultures and induce AHR and CAR signaling. (C) 2020 Elsevier B.V. All rights reserved.

5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.