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Autophagy stimulates apoptosis in HER2-overexpressing breast cancers treated by lapatinib
Xingmei Zhu1, Lin Wu, Hongyu Qiao
1Department of Pharmaceutical Chemistry, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Abstract:
HER2-overexpressing breast cancers often show hyperactivation of the HER2/AKT/mTOR signaling pathway. Lapatinib is an oral dual tyrosine kinase inhibitor (TKI) that targets both EGFR and HER2 to inhibit the proliferation of breast cancer cells. However, it is obscure whether and how lapatinib could induce autophagy in breast cancer cells, an important cell response with drug treatment. In this study, we investigated the apoptosis and the autophagy in the HER2-overexpressing breast cancer cells BT474 and AU565 treated with lapatinib, and further examined their relationship. Lapatinib inhibited the proliferation and the rate of DNA synthesis in HER2-positive cells, as observed by MTT, colony formation and EDU assays. Lapatinib not only induced apoptosis accompanied by an increased expression of cleaved Caspase-3 and cleaved PARP, but it also induced autophagy in vitro, as confirmed by electron microscopy (EM), acridine orange (AO) staining and LC3-II expression. Meanwhile, lapatinib inhibited the phosphorylation of HER2, AKT, mTOR, and p70S6K, whereas that of AMPK was activated. When the cells were pre-incubated with 3-Methyladenine (3-MA), the specific autophagy inhibitor, the growth inhibitory ratio and apoptosis rate were frustrated, whereas colony formation and DNA synthesis ability were encouraged. In addition, 3-MA application could up-regulate Caspase-3 and PARP expression, compared with the treatment with lapatinib alone. The addition of 3-MA could attenuate the inhibitory role on HER2/AKT/mTOR pathway and the active role on AMPK that was raised by lapatinib. Therefore, lapatinib simultaneously induced both apoptosis and autophagy in the BT474 and AU565 cells, and in these settings, autophagy facilitates apoptosis.
Insights
Lapatinib induces both apoptosis and autophagy in HER2-overexpressing breast cancer cells. Autophagy, a cellular response, appears to enhance the effectiveness of lapatinib in promoting cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- HER2-overexpressing breast cancers exhibit hyperactive HER2/AKT/mTOR signaling.
- Lapatinib, a dual tyrosine kinase inhibitor (TKI), targets EGFR and HER2 to impede cancer cell proliferation.
- The role of lapatinib in inducing autophagy in breast cancer cells remains unclear.
Purpose of the Study:
- To investigate the induction of apoptosis and autophagy by lapatinib in HER2-overexpressing breast cancer cells (BT474 and AU565).
- To examine the relationship between lapatinib-induced apoptosis and autophagy.
- To elucidate the underlying molecular mechanisms, including the HER2/AKT/mTOR pathway and AMPK activation.
Main Methods:
- Cell proliferation and DNA synthesis assessed using MTT, colony formation, and EDU assays.
- Apoptosis markers (cleaved Caspase-3, cleaved PARP) and autophagy markers (LC3-II) were evaluated.
- Electron microscopy (EM) and acridine orange (AO) staining confirmed autophagy.
- Western blotting analyzed signaling pathway phosphorylation (HER2, AKT, mTOR, p70S6K, AMPK).
- Autophagy inhibition using 3-Methyladenine (3-MA) assessed its impact on lapatinib's effects.
Main Results:
- Lapatinib significantly inhibited proliferation and DNA synthesis in HER2-positive cells.
- Lapatinib induced both apoptosis and autophagy, evidenced by increased cleaved Caspase-3/PARP and LC3-II expression, respectively.
- Lapatinib suppressed HER2/AKT/mTOR signaling while activating AMPK.
- Inhibition of autophagy by 3-MA attenuated lapatinib's anti-proliferative and pro-apoptotic effects, while promoting colony formation and DNA synthesis.
- 3-MA also reversed lapatinib's effects on signaling pathways and AMPK activation.
Conclusions:
- Lapatinib simultaneously induces apoptosis and autophagy in HER2-overexpressing breast cancer cells.
- Autophagy plays a crucial role in facilitating lapatinib-induced apoptosis in these cancer cells.
- Targeting the HER2/AKT/mTOR pathway and modulating autophagy presents a potential therapeutic strategy for HER2-positive breast cancer.
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