Click the blue words above to follow us
Good article recommendation
This paper is from a review in the Journal of China Pharmaceutical University, Vol. 51, No. 1, 2019, the research progress of lipid metabolism in non-small cell lung cancer.
Abstract: Recently, more and more researchers pay attention to the reprogramming of metabolism in tumor cells. Lipid metabolism not only plays an important role in the process of cell growth, apoptosis, movement and membrane homeostasis, but also participates in the regulation of body chemotherapy response, tumor microenvironment, tumor immunity and drug resistance and other biological processes. This paper reviews the research progress of fatty acid, cholesterol and phospholipid metabolism in non-small cell lung cancer in recent years, in order to provide new ideas for the prevention, early diagnosis and treatment of non-small cell lung cancer.
Key words: non-small cell lung cancer; lipid metabolism; lung cancer treatment; lipid regulation
The incidence rate and mortality of lung cancer are the first place in the malignant tumor. Histologically, lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC includes squamous cell carcinoma (SCC), adenocarcinoma (adenocarcinoma) and large cell carcinoma, accounting for about 85% of all lung cancer patients. In the process of treatment, serious adverse reactions of chemotherapy drugs, high drug resistance rate of targeted drugs and tumor immune tolerance microenvironment all bring many challenges to the treatment of NSCLC, so it is urgent to seek new ideas and strategies for the treatment of NSCLC.
Lipid metabolism can produce a variety of bioactive intermediates, which are produced by activating multiple signaling pathways, and can also regulate multiple signaling pathways, and play an important role in regulating cell growth, proliferation, differentiation, survival, apoptosis, inflammation, movement and membrane homeostasis. The same lipid metabolism disorder will change the composition and permeability of cell membrane, leading to the occurrence and development of a variety of tumors. Abnormal lipid metabolism has been found in colon cancer, breast cancer, lung cancer, prostate cancer and other tumors. This paper focuses on the relationship between endogenous lipid metabolism and non-small cell lung cancer.
Fatty acid metabolism and non-small cell lung cancer
In tumor cells, the high rate of de novo synthesis to produce a large number of monounsaturated fatty acids (MUFA) is considered to be the third typical tumor feature after the metabolic changes of glucose and glutamine. The fatty acids in cells are usually stored in the form of triglycerides (TGs) in lipid droplets, and free fatty acids are released by ATGL, HSL and MAGL. The first step of fatty acid synthesis is mediated by acetyl CoA carboxylase (ACC). In mammals, ACC is encoded by two related enzymes, acc1 and ACC2, which catalyze the formation of malonyl COA from acetyl coa. When cell energy is low, AMP level is higher than ATP level. Amp activated protein kinase (AMPK) phosphorylates and inactivates acc1 and ACC2, which promotes fatty acid oxidation and restores bioenergy homeostasis. On the contrary, phd3 hydroxylated and activated ACC2, which inhibited mitochondrial fatty acid oxidation. It can be seen that the process of fatty acid oxidation is regulated by AMPK and phd3.
Fatty acid synthetase (FASN) can catalyze acetyl coenzyme A or malonyl coenzyme A to produce fatty acids, and it is also one of the key enzymes in fatty acid synthesis and metabolism. It is worth noting that FASN has been shown to interact with caveolin-1, a palmitoylated lipid raft protein, in breast and pancreatic cancer, so that targeting FASN can not only inhibit tumor growth, but also promote tumor cell migration through a caveolin-1-dependent pathway. Epidermal growth factor receptor (EGFR) palmitoylation is specifically expressed in NSCLC with mutant EGFR and resistance to tyrosine kinase inhibitor (TK1). Mutant EGFR can activate FASN mediated by sterol regulatory element binding protein 1, which in turn promotes EGFR palmitoylation and TK1 resistance, which can be inhibited by orlistat, a selective inhibitor of FASN.
In addition to de novo synthesis, cells can also absorb fatty acids from the external environment through cell differentiation 36 (CD36). It was found that CD36, the protein responsible for fatty acid intake, is a marker of tumor cells with metastatic potential, and its prognosis is poor. It can be seen that CD36 may be a potential target to inhibit the metastasis of tumor cells. Up regulation of fatty acid binding protein (FABP) is another mechanism to promote lipid uptake by tumor cells (see Figure 1). It has been found that FABP3 and FABP4 are highly expressed in NSCLC, and have a significant correlation with the stage of advanced tumor lymph node metastasis (TNM), and have a negative correlation with the overall survival rate of patients with non-small cell lung cancer.
Cholesterol metabolism and non-small cell lung cancer
Sterol regulatory element binding protein (SREBP) and liver X receptor (LXRs) are key regulators of cholesterol homeostasis. Three SREBP subtypes can be expressed in mammalian cells. SREBP-1a, SREBP-1c and SREBP-2. SREBP-1a and 1C are encoded by the gene srebf1. SREBP-1c mainly regulates the expression of genes needed for fatty acid synthesis, while SREBP-1a can regulate fatty acid and cholesterol synthesis and cholesterol intake. SREBP-2 encoded by SREBF2 gene has relative specificity in regulating cholesterol synthesis and uptake. So SREBP2 is very important for cholesterol metabolism of tumor cells. The decrease of cholesterol in the endoplasmic reticulum will trigger the transfer of the complex of SREBP2 and SREBP cleavage activating protein (SCAP) from the endoplasmic reticulum to Golgi body, and then SREBP2 is cleaved and released, and its NH2-terminal transcription factors enter into the cell nucleus to activate the transcription of HMGCR, the synthesis gene of cholesterol, and promote the uptake of cholesterol through LDL receptor. The over accumulation of cholesterol will lead to the up regulation of LXRs, and then activate ABCA1, ABCG1, etc. to regulate cholesterol efflux (see Figure 2).
The cholesterol transporter NPC1L1 is another protein that mediates the influx of cholesterol. It is located on the membrane of intestinal epithelial cells and participates in the absorption process of free cholesterol into intestinal epithelial cells. NPC1L1 gene knockout can prevent the occurrence of E.coli related carcinogenesis by down regulating plasma cholesterol, inflammatory response, β - Catenin, p-c-jun and p-ERK levels. However, its role in NSCLC has not been reported yet. In view of its important role in cholesterol metabolism, it is speculated that NPC1L1 gene knockout may be related to the occurrence of NSCLC.
Phospholipid metabolism and non-small cell lung cancer
Phospholipid bimolecular layer constitutes the scaffold of cell membrane, which plays an important role in the process of controlling material in and out and signal transmission. The abnormal phospholipid level is related to the occurrence and development of many diseases. At present, the research on the relationship between phospholipids and tumor mainly focuses on phospholipids as biomarkers. Acid sphingomyelinase (ASM) is a key enzyme in the metabolism of sphingolipids. It mainly exists in lysosomes and can catalyze the decomposition of sphingomyelin into ceramide and choline phosphate, in which ceramide produces sphingosine under the action of acid ceramide kinase. The phosphorylated sphingosine 1-phosphate sphingosine (S1P) has the opposite biological function with ceramide, and both of them can be in vivo When S1P content is higher than ceramide, the cells will develop into tumor cells. Clinical sample analysis showed that ASM activity increased in the blood and lung tumor tissues of patients with adenocarcinoma and squamous cell carcinoma. ASM knockout can increase the ratio of sphingomyelin and ceramide content, and promote the apoptosis of H520 cells. Further research indicated that the number of activated T cells and cytokine receptors in tumor cells increased after ASM knockout, suggesting that ASM may be NSCLC immune The new effective target of therapy.
4. The current situation of the application of drugs for regulating lipid metabolism disorder of NSCLC
4.1 lipid lowering drugs
In recent years, there are more and more researches on lipid-lowering drugs such as statins used alone or in combination with therapeutic drugs. Statins are HMGR inhibitors, which can inhibit intracellular mevalonate by competitively inhibiting endogenous cholesterol synthesis rate limiting enzyme, so as to reduce intracellular cholesterol synthesis. A meta-analysis of 19974 lung cancer patients from 2007 to 2011 showed that the use of atorvastatin and simvastatin after diagnosis can significantly improve the survival rate of patients. As the first generation of statins, lovastatin can not only inhibit HMGR, but also block cell cycle and inhibit NSCLC by inhibiting MCM2. In addition, inhibition of SCD1 activity has also been shown to reduce the survival rate of NSCLC cells. The combination of g-ppt (ginsenoside derivative) and gefitinib can significantly reverse the phenomenon of gefitinib resistance.
4.2 drugs regulating lipid peroxidation
Curcumin has the effects of regulating blood lipid, anti-tumor, anti-inflammatory and anti-oxidation. It has been reported in many tumors, including lung cancer. Curcumin can inhibit the occurrence and development of various tumors by stimulating PPAR γ - lxr-abca1 pathway mediated cholesterol efflux of adipocytes. ROS, Ca2 + and ER stress increased in lung cancer cells exposed to curcumin. These signals lead to the loss of mitochondrial membrane potential and eventually the activation of caspase 3. Similarly, gingerone can increase the sensitivity of NSCLC to cisplatin chemotherapy by promoting the expression of p53 and inducing the activation of caspase 3 and caspase 9 in mitochondria. Quercetin is a kind of polyphenol flavonoid. It has been proved that quercetin can significantly improve the non enzyme antioxidant capacity of plasma, reduce lipid peroxidation, protect the oxidative damage caused by adriamycin and docetaxel in the treatment of breast cancer, and also enhance the chemical sensitivity of lung cancer cell lines A549 and H460 to gemcitabine by inhibiting HSP70. In addition, berberine caused the imbalance of Bax and Bcl-2 content by increasing the production of active oxygen, which led to the destruction of mitochondrial membrane potential. Activated caspase-9 and caspase-3 cracked PARP and led to A549 cell apoptosis.
5 Summary and Prospect
Abnormal lipid metabolism, especially a large number of fatty acids, can provide tumor cells with membrane components and lipid signaling molecules needed for proliferation. Although preclinical studies and clinical trials have revealed the important role of lipid metabolism in tumor growth and metastasis, most of the studies focused on one aspect of lipid metabolism, and did not fully consider its dynamic integrity and the complex control effect of environmental conditions. Further research is needed to investigate whether tumor cells continue to maintain metabolic characteristics and processes such as de novo synthesis under different stimulation conditions.
Chang Hui, Zhang Yameng, Ding Xuansheng. Research progress of lipid metabolism in non-small cell lung cancer [J]. Journal of China Pharmaceutical University, 2020,51 (1): 107-113
He Huiqin
Chen Ling, Gu Kai, Zou Xu
This article is the original of Journal of China Pharmaceutical University. Welcome to share it. If any other media or website needs to be reprinted, it should be indicated in the front of the text that it is from Journal of China Pharmaceutical University.
Poke "read the original" and charge it!