Endoplasmic reticulum stress contributes to several diseases such as neurodegenerative disorders and diabetes. In the previous report, we found that phosphatidylinositol 3-kinase (PI3K) down-regulation is important for inducing CHOP expression, an endoplasmic reticulum stress-induced transcription factor. In the present study, we investigated the effect of 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor, on PI3K inhibitor-induced CHOP expression. We found that AEBSF completely inhibited PI3K inhibitor-induced CHOP expression at both mRNA and protein levels. It is suggested that AEBSF is an important drug from a pharmacological point of view and the results may have important implications for understanding endoplasmic reticulum stress-related diseases.