Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer

Pengyu Geng; Jinhui Zhao; Qi Li; Xiaolin Wang; Wangshu Qin; Ting Wang; Xianzhe Shi; Xinyu Liu; Jia Chen; Hongdeng Qiu; Guowang Xu

doi:10.3390/ijms242317046

Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer

Int J Mol Sci. 2023 Dec 1;24(23):17046. doi: 10.3390/ijms242317046.

Authors

Pengyu Geng^{1

2}, Jinhui Zhao^{1

2}, Qi Li^{1

2}, Xiaolin Wang^{1

2}, Wangshu Qin^{1

2}, Ting Wang^{1

2}, Xianzhe Shi^{1

2}, Xinyu Liu^{1

2}, Jia Chen³, Hongdeng Qiu³, Guowang Xu^{1

2}

Affiliations

¹ CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
² Liaoning Province Key Laboratory of Metabolomics, Dalian 116023, China.
³ CAS Key Laboratory of Chemistry of Northwestern Plant Resources, Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China.

Abstract

Lung cancer is a malignant tumor with one of the highest morbidity and mortality rates in the world. Approximately 80-85% of lung cancer is diagnosed as non-small lung cancer (NSCLC), and its 5-year survival rate is only 21%. Cisplatin is a commonly used chemotherapy drug for the treatment of NSCLC. Its efficacy is often limited by the development of drug resistance after long-term treatment. Therefore, determining how to overcome cisplatin resistance, enhancing the sensitivity of cancer cells to cisplatin, and developing new therapeutic strategies are urgent clinical problems. Z-ligustilide is the main active ingredient of the Chinese medicine Angelica sinensis, and has anti-tumor activity. In the present study, we investigated the effect of the combination of Z-ligustilide and cisplatin (Z-ligustilide+cisplatin) on the resistance of cisplatin-resistant lung cancer cells and its mechanism of action. We found that Z-ligustilide+cisplatin decreased the cell viability, induced cell cycle arrest, and promoted the 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 phospholipid phosphatase 1 (PLPP1). A further study showed that PLPP1 expression was positively correlated with good prognosis, whereas the knockdown of PLPP1 abolished the effects of Z-ligustilide+cisplatin on cell cycle and apoptosis. Specifically, Z-ligustilide+cisplatin inhibited the activation of protein kinase B (AKT) by reducing the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP₃). Z-ligustilide+cisplatin induced cell cycle arrest and promoted the cell apoptosis of cisplatin-resistant lung cancer cells by inhibiting PLPP1-mediated phospholipid synthesis. Our findings demonstrate that the combination of Z-Ligustilide and cisplatin is a promising approach to the chemotherapy of malignant tumors that are resistant to cisplatin.

Keywords: PLPP1; Z-Ligustilide; cell apoptosis; cell cycle arrest; cisplatin resistance; phospholipid synthesis.

MeSH terms

4-Butyrolactone / pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation
Cisplatin* / pharmacology
Cisplatin* / therapeutic use
Drug Resistance, Neoplasm / genetics
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Phospholipids / pharmacology

Substances

Cisplatin
ligustilide
4-Butyrolactone
Phospholipids

Abstract

MeSH terms

Substances

Grants and funding