Please wait a minute...
J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (1): 17-22    DOI: 10.3724/zdxbyxb-2021-0054
Interaction between RAS gene and lipid metabolism in cancer
ZHANG Mingquan(),PAN Junchen,HUANG Peng()
Cancer Center,Sun Yat-Sen University,Guangzhou 510060,China
Download: HTML( 20 )   PDF(3281KB)
Export: BibTeX | EndNote (RIS)      


The RAS gene is frequently mutated and abnormally activated in many cancers,and plays an important role in cancer development. Metabolic reprogramming occurs in malignant tumors,which can be one of the key targets for anti-tumor therapy. RAS gene can regulate lipid metabolism through AKT-mTORC1 single axis or multiple pathways,such as lipid synthesis pathways and degradation pathways. Similarly,lipid metabolism can also modify and activate RAS protein and its downstream signaling pathways. This article overviews the current research progress on the interaction between lipid metabolism and RAS,to provide insight in therapeutic strategies of lipid metabolism for RAS-driven tumors.

Key wordsRAS gene      Lipid metabolism      Tumor      Therapy      Review     
Received: 14 December 2020      Published: 14 May 2021
CLC:  R730.23  
Corresponding Authors: HUANG Peng     E-mail:;
Cite this article:

ZHANG Mingquan,PAN Junchen,HUANG Peng. Interaction between RAS gene and lipid metabolism in cancer. J Zhejiang Univ (Med Sci), 2021, 50(1): 17-22.

URL:     OR


RAS基因是恶性肿瘤中常见的驱动基因,在多种恶性肿瘤中高频率突变并异常活化,是驱动肿瘤发生发展的重要因素。代谢重编程作为恶性肿瘤重要特征之一,是抗肿瘤治疗的关键靶点。 RAS基因可通过蛋白激酶B/哺乳动物雷帕霉素靶蛋白复合物1信号轴或其他多条信号通路调控脂代谢,如脂质合成途径和降解途径等。同样,脂代谢也能修饰并激活RAS蛋白及其下游信号通路。因此,本文概述了现阶段脂代谢与 RAS之间相互调控的研究,旨在为靶向脂代谢在 RAS驱动型肿瘤的临床应用提供思路。

关键词: RAS基因,  脂代谢,  肿瘤,  治疗,  综述 
Figure 1 Molecular switch function of RAS
Figure 2 Main pathways of RAS regulating lipid metabolism
Figure 3 The regulation of lipids on RAS activity
[1]   CANON J, REX K, SAIKI A Y, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity[J]. Nature, 2019, 575(7781): 217-223.
doi: 10.1038/s41586-019-1694-1
[2]   SPIEGEL J, CROMM P M, ZIMMERMANN G, et al. Small-molecule modulation of Ras signaling[J]. Nat Chem Biol, 2014, 10(8): 613-622.
doi: 10.1038/nchembio.1560
[3]   PAPKE B, DER C J . Drugging RAS:know the enemy[J]. Science, 2017, 355(6330): 1158-1163.
doi: 10.1126/science.aam7622
[4]   HANAHAN D, WEINBERG R A . Hallmarks of cancer:the next generation[J]. Cell, 2011, 144(5): 646-674.
doi: 10.1016/j.cell.2011.02.013
[5]   COX A D, FESIK S W, KIMMELMAN A C, et al. Drugging the undruggable RAS:mission possible?[J]. Nat Rev Drug Discov, 2014, 13(11): 828-851.
doi: 10.1038/nrd4389
[6]   WATERS A M, DER C J . KRAS:the critical driver and therapeutic target for pancreatic cancer[J]. Cold Spring Harb Perspect Med, 2018, 8(9): a031435.
doi: 10.1101/cshperspect.a031435
[7]   SNAEBJORNSSON M T, JANAKI-RAMAN S, SCHULZE A . Greasing the wheels of the cancer machine:the role of lipid metabolism in cancer[J]. Cell Metab, 2020, 31(1): 62-76.
doi: 10.1016/j.cmet.2019.11.010
[8]   R?HRIG F, SCHULZE A . The multifaceted roles of fatty acid synthesis in cancer[J]. Nat Rev Cancer, 2016, 16(11): 732-749.
doi: 10.1038/nrc.2016.89
[9]   MEDES G,THOMAS A,WEINHOUSE S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro[J]. Cancer Res,1953,13:27–29 .
[10]   BROWN M S, GOLDSTEIN J L . A receptor-mediated pathway for cholesterol homeostasis[J]. Science, 1986, 232(4746): 34-47.
doi: 10.1126/science.3513311
[11]   KAZANTZIS M, STAHL A . Fatty acid transport proteins,implications in physiology and disease[J]. BioChim Biophysica Acta, 2012, 1821(5): 852-857.
doi: 10.1016/j.bbalip.2011.09.010
[12]   CAMARDA R, ZHOU A Y, KOHNZ R A, et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer[J]. Nat Med, 2016, 22(4): 427-432.
doi: 10.1038/nm.4055
[13]   LIN H, PATEL S, AFFLECK V S, et al. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells[J]. Neuro Oncology, 2017, 19(1): 43-54.
doi: 10.1093/neuonc/now128
[14]   HORTON J D, SHAH N A, WARRINGTON J A, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes[J]. Proc Natl Acad Sci USA, 2003, 100(21): 12027-12032.
doi: 10.1073/pnas.1534923100
[15]   GONZáLEZ A, HALL M N, LIN S C, et al. AMPK and TOR:the yin and yang of cellular nutrient sensing and growth control[J]. Cell Metab, 2020, 31(3): 472-492.
doi: 10.1016/j.cmet.2020.01.015
[16]   RICOULT S J H, YECIES J L, BEN-SAHRA I, et al. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP[J]. Oncogene, 2016, 35(10): 1250-1260.
doi: 10.1038/onc.2015.179
[17]   KAMPHORST J J, CROSS J R, FAN J, et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids[J]. Proc Natl Acad Sci USA, 2013, 110(22): 8882-8887.
doi: 10.1073/pnas.1307237110
[18]   LIANG C, QIN Y, ZHANG B, et al. Metabolic plasticity in heterogeneous pancreatic ductal adenocarcinoma[J]. BioChim Biophysica Acta, 2016, 1866(2): 177-188.
doi: 10.1016/j.bbcan.2016.09.001
[19]   CAO J Y, DIXON S J . Mechanisms of ferroptosis[J]. Cell Mol Life Sci, 2016, 73(11-12): 2195-2209.
doi: 10.1007/s00018-016-2194-1
[20]   DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis:an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072.
doi: 10.1016/j.cell.2012.03.042
[21]   YANG W S, STOCKWELL B R . Ferroptosis:death by lipid peroxidation[J]. Trends Cell Biol, 2016, 26(3): 165-176.
doi: 10.1016/j.tcb.2015.10.014
[22]   ZHENG J, CONRAD M . The metabolic underpinnings of ferroptosis[J]. Cell Metab, 2020, 32(6): 920-937.
doi: 10.1016/j.cmet.2020.10.011
[23]   SHIOZAKI A, IITAKA D, ICHIKAWA D, et al. xCT,component of cysteine/glutamate transporter,as an independent prognostic factor in human esophageal squamous cell carcinoma[J]. J Gastroenterol, 2014, 49(5): 853-863.
doi: 10.1007/s00535-013-0847-5
[24]   LUCAS L, DEL PESO L, RODRíGUEZ P, et al. Ras protein is involved in the physiological regulation of phospholipase D by platelet derived growth factor[J]. Oncogene, 2000, 19(3): 431-437.
doi: 10.1038/sj.onc.1203323
[25]   RAMíREZ DE MOLINA A, PENALVA V, LUCAS L, et al. Regulation of choline kinase activity by Ras proteins involves Ral–GDS and PI3K[J]. Oncogene, 2002, 21(6): 937-946.
doi: 10.1038/sj.onc.1205144
[26]   GAULT C R, EBLEN S T, NEUMANN C A, et al. Oncogenic K-Ras regulates bioactive sphingolipids in a sphingosine kinase 1-dependent manner[J]. J Biol Chem, 2012, 287(38): 31794-31803.
doi: 10.1074/jbc.M112.385765
[27]   SALIAKOURA M, ROSSI SEBASTIANO M, POZZA- TO C, et al. PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia[J]. Nat Cell Biol, 2020, 22(11): 1382-1395.
doi: 10.1038/s41556-020-00592-8
[28]   WILLUMSEN B M, CHRISTENSEN A, HUBBERT N L, et al. The p21 ras C-terminus is required for transformation and membrane association[J]. Nature, 1984, 310(5978): 583-586.
doi: 10.1038/310583a0
[29]   WRIGHT L P, PHILIPS M R . Thematic review series:lipid posttranslational modifications CAAX modification and membrane targeting of Ras[J]. J Lipid Res, 2006, 47(5): 883-891.
doi: 10.1194/jlr.R600004-JLR200
[30]   SCHMIDT W K, TAM A, FUJIMURA-KAMADA K, et al. Endoplasmic reticulum membrane localization of Rce1p and Ste24p,yeast proteases involved in carboxyl-terminal CAAX protein processing and amino-terminal a-factor cleavage[J]. Proc Natl Acad Sci USA, 1998, 95(19): 11175-11180.
doi: 10.1073/pnas.95.19.11175
[31]   WHYTE D B, KIRSCHMEIER P, HOCKENBERRY T N, et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors[J]. J Biol Chem, 1997, 272(22): 14459-14464.
doi: 10.1074/jbc.272.22.14459
[32]   HANCOCK J F, PATERSON H, MARSHALL C J . A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane[J]. Cell, 1990, 63(1): 133-139.
doi: 10.1016/0092-8674(90)90294-o
[33]   GOODWIN J S, DRAKE K R, ROGERS C, et al. Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway[J]. J Cell Biol, 2005, 170(2): 261-272.
doi: 10.1083/jcb.200502063
[1] SHAO Yiming,SU Lide,HAO Rui,WANG Qianqian,NARANMANDURA Hua. Advances on molecular mechanism of hepatitis B virus-induced hepatocellular carcinoma[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 113-122.
[2] HAN Hengyi,FENG Fan,LI Haitao. Research advances on epigenetics and cancer metabolism[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 1-16.
[3] CHEN Fei,YU Min,ZHONG Yonghong,HUA Wen,HUANG Huaqiong. The role of neutrophils in asthma[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 123-130.
[4] YAN Jing,ZHANG Tingting,ZHAO Kui. Application of molecular probes in nuclear imaging of neuroendocrine tumors[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 131-137.
[5] HU Xinyang,JIN Hongchuan,ZHU Liyuan. Effect of glutamine metabolism on chemoresistance and its mechanism in tumors[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 32-40.
[6] MENG Ying,WANG Qifei,LYU Zhimin. Cholesterol metabolism and tumor[J]. J Zhejiang Univ (Med Sci), 2021, 50(1): 23-31.
[7] YANG Zeran,ZHANG Xin,MA Jie,JIN Li,HE Xujun. Expression of tumor-associated vascular insulin receptor in colorectal cancer and its relationship with tumor pathological features[J]. J Zhejiang Univ (Med Sci), 2020, 49(6): 725-731.
[8] ZHU Huiqi,YING Kejing. Tissue factors and venous thromboembolism in cancer patients[J]. J Zhejiang Univ (Med Sci), 2020, 49(6): 772-778.
[9] LIN Cuicui,CHEN Zhengyun,WANG Chunyan,XI Yongmei. Research progress on biomarkers for endometriosis based on lipidomics[J]. J Zhejiang Univ (Med Sci), 2020, 49(6): 779-784.
[10] LIU Yun,LI Kaikai,WU Juan,LI Hezhou,GENG Xiaoduan,GU Yachuan. Morbidity of congenital heart disease in children with anorectal malformations and related treatment[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 597-602.
[11] LI Mengyao,LIU Pan,KE Yuehai,ZHANG Xue. Research progress on macrophage in radiation induced lung injury[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 623-628.
[12] HAN Xue,JIANG Guojun,SHI Qiaojuan. Effects of antihyperglycemics on endothelial progenitor cells[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 629-636.
[13] DUAN Runping,XU Yesheng,ZHENG Libin,YAO Yufeng. Research progress on etiologic diagnosis of ocular viral diseases[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 644-650.
[14] WU Wei,XU Jian. Research progress on the role of pentraxin 3 in polycystic ovary syndrome[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 637-643.
[15] XU Qinglin,LOU Guodong,WANG Tiantian,ZHANG Lisan. Advances in treatment of narcolepsy[J]. J Zhejiang Univ (Med Sci), 2020, 49(4): 419-424.