Abstract
Gastric cancer (GC) is one of the most prevalent cancers worldwide. Trastuzumab has been approved for the treatment of metastatic GC, gastroesophageal junction cancer, and breast cancer. However, the mechanisms involved in trastuzumab-induced GC cell apoptosis remain largely unknown. In this study, we investigated the underlying mechanisms of trastuzumab-mediated suppression of GC cell growth both in vitro and in vivo. We found that trastuzumab treatment induces p53 upregulated modulator of apoptosis (PUMA) expression in GC cells, through the NF-κB pathway following AKT inhibition and glycogen synthase kinase 3β (GSK3β) activation. We also observed that PUMA was necessary for trastuzumab-induced apoptosis in GC cells. Moreover, PUMA deficiency suppressed apoptosis and the antitumor effect of trastuzumab in xenograft models. Finally, computerized tomography (CT) and immunohistochemistry results showed that patients with increased activation of PUMA were more sensitive to trastuzumab treatment than those with low PUMA expression. These results indicate that trastuzumab induces PUMA-dependent apoptosis and inhibits tumor growth in GC, suggesting that PUMA plays a critical role in mediating the antitumor effects of trastuzumab in GC. PUMA induction may be used as a marker of trastuzumab sensitivity.