Abstract
Autophagy is one of the induced mechanisms in metastatic cancer to escape death due to starvation, hypoxia, metabolic stresses, chemotherapy, and radiation. Some publications have revealed that chemotherapy combined with autophagy inhibitor will overcome drug resistance. We modified AS2 cells with PTEN overexpression, mTOR knockdown, or Keap1 knockdown, and made modification of A549 cells with PTEN knockdown, Atg5 knockdown, and Keap1 overexpression. Our study was aimed toward an exploration of how autophagy modulates Keap1, ROS generation, and vinorelbine-induced apoptosis in these cell lines. We found that lung cancer PC14PE6/AS2 (AS2) had higher mTOR and Akt and also lower PTEN expression than A549 cells. Descended autophagy was demonstrated with more decreased p62 accumulation and LC3 II conversion in AS2 cells as compared to A549 cells. The A549 cells had lower Keap1/Nrf2 and more active anti-oxidant response element (ARE) activity than the AS2 cells. We modified AS2 cells with PTEN overexpression, mTOR knockdown, Keap1 knockdown, and revealed amplified p62 and LC3 expression accompanied with decreased Akt, Keap1, ROS, and vinorelbine-induced apoptosis. Declined p62, LC3 expression were accompanied with increased Akt, Keap1, ROS, and vinorelbine-induced apoptosis after modification of A549 cells with PTEN knockdown, Atg5 knockdown, and Keap1 overexpression. Keap1 overexpression lowered ARE levels in A549 cells, and ARE level exhibited up-growth in Keap1 knockdown AS2 cells. The autophagy inhibitor caused more ROS generation and vinorelbine-induced apoptosis in the A549 and CL1-5 cells. According to these findings, autophagy regulates vinorelbine sensitivity by continuing Keap1-mediated ROS generation in lung adenocarcinoma cells.
Highlights
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Lung cancer causes many deaths worldwide, and there are increasing numbers of publications exploring the relationship between lung cancer and autophagy
We examined several regulators of autophagy in lung cancer A549 and AS2 cells
We summarized some regulators of autophagy, including autophagy-suppressing factors and autophagy-promoting factors (PTEN)[8]
Summary
Lung cancer causes many deaths worldwide, and there are increasing numbers of publications exploring the relationship between lung cancer and autophagy. Autophagy has a dual role in lung cancer, including being an inhibitor of initial oncogenesis and facilitating tumor progression[1]. Autophagy can be divided into three major intracellular pathways, including macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA)[3]. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) regulate intracellular signal transduction and sustain autophagy. P62 is an autophagy adaptor protein to regulate the degradation of the proteins accumulated in inclusion body[5]. The tumor suppressor gene phosphatase and tensin homolog (PTEN) was first identified in 1997, and a previous study revealed that 74% of protein expression is decreased or lost in lung cancer[6]. Because PTEN negatively regulates the PI3K-Akt-mTOR pathway, some targeted therapy has been developed to enhance its expression in tumors with PTEN loss[7].
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