Abstract
Abstract Background: Chemotherapy plays a major role in cancer therapy. Yet, one of its greatest obstacles is the development of chemotherapy resistance. Hence, understanding the molecular basis of chemoresistance is crucial to improve its therapeutic outcome. A close relationship between mitochondrial dynamic and cellular apoptosis has recently been identified. Mitochondrial fission is necessary for initiation of cellular apoptosis, whereas mitochondrial fusion is able to inhibit apoptosis. However, the association of mitochondrial fission and chemo-sensitivity has not been widely explored. Recently, mitochondrial protein MTP18 has been shown to promote mitochondrial fragmentation in various cancer cell lines. However, its role in apoptosis and chemotherapeutic resistance remains elusive. Here, we aimed to detect 1) whether MTP18 is able to regulate mitochondrial fission and apoptosis in gastric cancer cells, and 2) by which mechanism it regulates these events. Methods and Results: Doxorubicin is one of the most widely used chemotherapeutic agents in variety of cancers. Mitochondrial staining with MitoTracker Red CMXRos revealed doxorubicin was able to induce mitochondrial fission both in vitro and in vivo gastric cancer models. We observed doxorubicin led to a decreasing level of MTP18 expression in gastric cancer cell lines, and this effect was concentration- and time-dependent. To understand the role of MTP18 in doxorubicin-induced mitochondrial fission and apoptosis, endogenous MTP18 expression was knockdown using MTP18-shRNA. Strikingly, doxorubicin could not induce mitochondrial fission in gastric cancer cells transfected with MTP18-shRNA. On the other hand, upon enforced expression of MTP18, the same concentration of doxorubicin sensitized a significantly higher number of gastric cancer cells to undergo mitochondrial fission and apoptosis. These findings suggest that MTP18 is required for doxorubicin-induced mitochondrial fission and apoptosis. In exploring the molecular mechanism of MTP18, we found that MTP18 enriched dynamin-related protein Drp1 accumulation in mitochondria and mediated the signal of doxorubicin to induce mitochondrial fission. Drp1 accumulation in mitochondria caused the release of cytochrome-c to cytosol and subsequently promoted apoptosis. Conclusion: Taken together, our findings suggest that MTP18 induces mitochondrial fission and enhances apoptosis in gastric cancer cells, by promoting Drp1 accumulation in mitochondria. Thus, it is compelling us to conclude that MTP18 enhances doxorubicin sensitivity of gastric cancer cells by targeting mitochondrial fission machinery. Citation Format: Lynn Htet Htet Aung, Peifeng Li. The mitochondrial protein MTP18 enhances chemosensitivity by promoting mitochondrial fission. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 211.
Published Version
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