The EphB2 tumor suppressor induces autophagic cell death via concomitant activation of the ERK1/2 and PI3K pathways

Kallikrein‐8 inhibition attenuates Alzheimer's disease pathology in mice

“…EPHB2 induction appears to promote autophagy under neoplastic conditions [7,8]. We therefore asked whether KLK8 inhibition and the resulting EPHB2 protection are able to counteract autophagy deficits in the AD-affected brain.…”

“…EPHB2 signaling via trans-cellular communication with ephrin B2 ligand (EFNB2) is further of particular relevance for neuronal plasticity, as it coordinates axonal guidance [4] and controls synaptogenesis [5]. EPHB2 signal transduction is also known to induce angiogenesis [6] and autophagy [7,8] under neoplastic conditions.…”

Sorafenib and pemetrexed toxicity in cancer cells is mediated via SRC-ERK signaling

“…The mechanisms by which SRC or ERK1/2 signaling promote autophagy are not fully understood, though there are multiple manuscripts showing ERK1/2 signaling stimulates autophagic vesicle formation with diverse cellular outcomes. [34][35][36][37] It has been reported that AMPK activation, downstream of the pemetrexed target AICART in tumor cells can be enhanced by c-SRC signaling, providing a possible signaling pathway overlap between sorafenib and pemetrexed. 38 It is also known that autophagy is regulated by the reversible phosphorylation of multiple ATG family genes and it is probable that ERK1/2 acts to alter ATG protein phosphorylation that in turn facilitates an increase in vesicle formation.…”

The autophagic paradox in cancer therapy

“…In two different animal models, monoallelic loss of Beclin 1 promotes the development of spontaneous malignancies and hepatitis B virus-induced premalignant lesions whereas mice deficient in Atg4C/autophagin-3 show an increased susceptibility to develop carcinogen-induced fibrosarcomas (Yue et al, 2003;Marino et al, 2007). Autophagy has also been shown to promote cancer cell death or cell cycle arrest induced by various tumor suppressors, such as, FoxO1 (forkhead box protein O1), EphB2 (ephrin receptor B2) and TGFb (Kandouz et al, 2010;Suzuki et al, 2010;Zhao et al, 2010). A recent study also demonstrated that activation of autophagy inhibits invasion and migration of MDA-MB-231 cells, in which the effect could be blocked by LC3 silencing, suggesting that autophagy may negatively regulate cancer invasiveness (Indelicato et al, 2010).…”