${alpha}$-Mangostin is a xanthon derivative contained in the fruit hull of mangosteen (Garcinia mangostana L.), and the administration of ${alpha}$-Mangostin inhibited the growth of transplanted colon cancer, Her/CT26 cells which expressed Her-2/neu as tumor antigen. Although ${alpha}$-Mangostin was reported to have inhibitory activity against sarco/endoplasmic reticulum $Ca^{2+}$ ATPase like thapsigargin, it showed different activity for autophagy regulation. In the current study, we found that ${alpha}$-Mangostin induced autophagy activation in mouse intestinal epithelial cells, as GFP-LC3 transgenic mice were orally administered with 20 mg/kg of ${alpha}$-Mangostin daily for three days. However, the activation of autophagy by ${alpha}$-Mangostin did not significantly increase OVA-specific T cell proliferation. As we assessed ER stress by using XBP-1 reporter system and phosphorylation of $eIF2{alpha}$, thapsigargin-induced ER stress was significantly reduced by ${alpha}$-Mangostin. However, coadministration of thapsigargin with ${alpha}$-Mangostin completely blocked the antitumor activity of ${alpha}$-Mangostin, suggesting ER stress with autophagy blockade accelerated tumor growth in mouse colon cancer model. Thus the antitumor activity of ${alpha}$-Mangostin can be ascribable to the autophagy activation rather than ER stress induction.