Geng, P.; Zhao, J.; Li, Q.; Wang, X.; Qin, W.; Wang, T.; Shi, X.; Liu, X.; Chen, J.; Qiu, H.; Xu, G. Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer. Int. J. Mol. Sci.2023, 24, 17046.
Geng, P.; Zhao, J.; Li, Q.; Wang, X.; Qin, W.; Wang, T.; Shi, X.; Liu, X.; Chen, J.; Qiu, H.; Xu, G. Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer. Int. J. Mol. Sci. 2023, 24, 17046.
Geng, P.; Zhao, J.; Li, Q.; Wang, X.; Qin, W.; Wang, T.; Shi, X.; Liu, X.; Chen, J.; Qiu, H.; Xu, G. Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer. Int. J. Mol. Sci.2023, 24, 17046.
Geng, P.; Zhao, J.; Li, Q.; Wang, X.; Qin, W.; Wang, T.; Shi, X.; Liu, X.; Chen, J.; Qiu, H.; Xu, G. Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer. Int. J. Mol. Sci. 2023, 24, 17046.
Abstract
Z-ligustilide is a main active ingredient in the volatile oil of Angelica sinensis, a traditional Chinese medicine. Cisplatin is a commonly used chemotherapy drug for the treatment of lung cancer. Efficacy is often limited by the development of drug resistance after long-term treatment. Here, we investigated the effect of the combination of Z-ligustilide and cisplatin (Z-ligustilide+cisplatin) on resistance of cisplatin-resistant lung cancer cells and its action mechanism. Cell viability was analyzed by cell counting kit-8 (CCK-8) assay. Cell cycle and cell apoptosis were examined by flow cytometry assay. mRNA and protein levels of factors related to cell cycle and apoptosis were analyzed by real-time PCR and western blot. Liquid chromatography-mass spectrometry (LC-MS) analysis and RNA sequencing in A549, A549/DDP and A549/DDP cells treated with the Z-ligustilide+cisplatin were performed. The expression of PLPP1 was analyzed by the Cancer Genome Atlas (TCGA). The correlation between PLPP1 and prognosis was evaluated by immunohistochemistry and Kaplan-Meier (KM) plotter analysis. We found that Z-ligustilide+cisplatin could decrease the cell viability of cisplatin-resistant lung cancer cells. Z-ligustilide+cisplatin induced cell cycle arrest, and promoted cell apoptosis of cisplatin-resistant lung cancer cells. Metabolomics combined with transcriptomics revealed that Z-ligustilide+cisplatin inhibited phospholipid synthesis by upregulating the expression of PLPP1. Furthermore, PLPP1 expression was positively correlated with good prognosis. Knockdown of PLPP1 abolished the effects of Z-ligustilide+cisplatin on cell cycle and apoptosis. Z-ligustilide+cisplatin inhibited the activation of AKT by reducing the levels of PIP3 levels. Z-ligustilide+cisplatin induced cell cycle arrest and promoted cell apoptosis of cisplatin-resistant lung cancer cells by inhibiting PLPP1-mediated phospholipid synthesis.
Medicine and Pharmacology, Oncology and Oncogenics
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