Abstract
Abstract Unresectable colorectal liver metastases remain major unsolved issues and more effective regimens are urgently needed. During screening synergistic drug combinations for colon cancer therapy, we identified a novel multimodality treatment for colon cancer cells-chemotherapeutic agent melphalan in combination with proteasome inhibitor bortezomib and mTOR (mammalian target of rapamycin) inhibitor rapamycin. We showed in this study that melphalan triggered apoptosis, bortezomib induced both apoptosis and autophagy, rapamycin caused autophagy, and the combinatorial treatment induced synergistic apoptosis which was mediated through an increase in caspase activation. We observed that mitochondrial dysfunction induced by the combination was linked with altered cellular metabolism and induced AMP-activated protein kinase (AMPK) activation, and thus resulted in Beclin-1 phosphorylated at Ser 93/96. Interestingly, Beclin-1 phosphorylated at Ser 93/96 is sufficient to induce Beclin-1 cleavage by caspase 8 for switching off autophagy to achieve the synergistic induction of apoptosis. The multimodality treatment-induced Beclin-1 cleavage was abolished in Beclin-1 double mutant (D133A/D149A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. These observations provide a novel mechanism for AMPK induced apoptosis through interplay between autophagy and apoptosis. Citation Format: Xinxin Song, Seog-Young Kim, Lin Zhang, Yong J. Lee. Role of AMP-activated protein kinase in crosstalk between apoptosis and autophagy in human colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1345. doi:10.1158/1538-7445.AM2014-1345
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