Abstract
Breast cancer is still one of the most common cancers for women. Specified therapeutics are indispensable for optimal treatment. In previous studies, it has been shown that RL2, the recombinant fragment of human κ-Casein, induces cell death in breast cancer cells. However, the molecular mechanisms of RL2-induced cell death remain largely unknown. In this study, mechanisms of RL2-induced cell death in breast cancer cells were systematically investigated. In particular, we demonstrate that RL2 induces loss of mitochondrial membrane potential and cellular ATP loss followed by cell death in breast cancer cells. The mass spectrometry-based screen for RL2 interaction partners identified mitochondrial import protein TOM70 as a target of RL2, which was subsequently validated. Further to this, we show that RL2 is targeted to mitochondria after internalization into the cells, where it can also be found in the dimeric form. The importance of TOM70 and RL2 interaction in RL2-induced reduction in ATP levels was validated by siRNA-induced downregulation of TOM70, resulting in the partial rescue of ATP production. Taken together, this study demonstrates that RL2–TOM70 interaction plays a key role in RL2-mediated cell death and targeting this pathway may provide new therapeutic options for treating breast cancer.
Highlights
Breast cancer is still one of the most common tumorigenic diseases for women
The RL2–TOM70 interaction was validated by the so-called reverse approach of TOM70 immunoprecipitation from RL2 treated MDA-MB-231 or MCF-7 cells (Figure 4D,E; Figure S3B,C). These results provide strong evidence on RL2–TOM70 interaction and indicate that RL2 is targeted to the mitochondria after penetration into the cell
Previous studies have shown that Lactaptin and its recombinant analogue RL2 have strong antitumor effects in breast cancer, endometrial cancer, lung cancer and hepatoma cells [6,10]
Summary
Breast cancer is still one of the most common tumorigenic diseases for women. Radiation- and chemotherapy remain, until today, the most common approaches for breast cancer treatment. Various naturally occurring proteins or chemical compounds resulting from pharmacodynamical studies have been used to develop specific drugs for breast cancer [2,3]. Human milk was found to be a source of multiple bioactive peptides for the treatment of breast cancer. Some of these peptides were recently been utilized to engineer new antitumor drugs such as HAMLET [4], Lactoferrin [5] or Lactaptin [6]
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