脾虚是大肠癌细胞自噬和能量代谢异常的关键病机
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摘要
自噬是细胞的基本生命现象,维持着细胞内环境稳态,是人体气化功能的微观体现。脾虚则气化功能受损,细胞自噬功能异常。脾与线粒体功能相似,脾虚则线粒体氧化磷酸化受限,能量代谢障碍,促使肿瘤细胞有氧糖酵解,为肿瘤提供快速增殖的条件。大肠癌细胞在缺氧环境下,缺氧诱导因子促使自噬体相关蛋白表达上调,自噬活性增强,通过对能量代谢相关物质或通路的调控进而影响细胞能量代谢,促使肿瘤发展和转移。自噬可诱导放化疗抵抗,引起大肠癌耐药。通过健脾益气可调控大肠癌细胞自噬和能量代谢异常。
Autophagy is the basic life phenomenon of cells,which maintains the homeostasis of cells and is a microscopic manifestation of human gasification.Spleen deficiency is impaired in gasification and abnormal autophagy.The Spleen and mitochondria function similarly.The spleen deficiency is limited by mitochondrial oxidative phosphorylation,energy metabolism disorder,and promotes aerobic glycolysis of tumor cells,providing conditions for rapid proliferation of tumors.In the hypoxic environment of colorectal cancer cells,hypoxia-inducible factors promote the up-regulation of autophagosome-associated proteins,enhance autophagy activity,and affect the energy metabolism of cells through the regulation of energy metabolism related substances or pathways,and promote tumor development and metastasis.Autophagy can induce resistance to chemoradiotherapy and cause colorectal cancer resistance.The autophagy and abnormal energy metabolism of colorectal cancer cells can be regulated by strengthening the Spleen and replenishing Qi,and provides a new strategy for anti-cancer of traditional Chinese medicine.
Autophagy is the basic life phenomenon of cells,which maintains the homeostasis of cells and is a microscopic manifestation of human gasification.Spleen deficiency is impaired in gasification and abnormal autophagy.The Spleen and mitochondria function similarly.The spleen deficiency is limited by mitochondrial oxidative phosphorylation,energy metabolism disorder,and promotes aerobic glycolysis of tumor cells,providing conditions for rapid proliferation of tumors.In the hypoxic environment of colorectal cancer cells,hypoxia-inducible factors promote the up-regulation of autophagosome-associated proteins,enhance autophagy activity,and affect the energy metabolism of cells through the regulation of energy metabolism related substances or pathways,and promote tumor development and metastasis.Autophagy can induce resistance to chemoradiotherapy and cause colorectal cancer resistance.The autophagy and abnormal energy metabolism of colorectal cancer cells can be regulated by strengthening the Spleen and replenishing Qi,and provides a new strategy for anti-cancer of traditional Chinese medicine.
引文
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[38]丁宁,杨宇飞,刘羿男,等.健脾活血解毒法拆方含药血清对人大肠癌细胞HCT-116细胞的增殖抑制作用及其机制研究[J].中国实验方剂学杂志,2013,19(11):272-275.
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[2]SIEGEL R,MA J,ZOU Z,et al.Cancer statistics[J].Cancer J Clinicians,2014,64(1):9-29.
[3]CHEN W,ZHENGR S,ZHANG S,et al.Report of cancer incidence and mortality in China,2012[J].China Cancer,2016,25(1):1-8.
[4]林胜友,沈敏鹤,蓝继,等.780例大肠癌中医证候与生存期的相关性分析[J].中医杂志,2012,53(5):410-412.
[5]侯风刚,岑怡,贯剑.肠癌中医症状证候临床调查分析[J].辽宁中医药大学学报,2010,12(1):32-34.
[6]JIANG P,MIZUSHIMA N.Autophagy and human diseases[J].Cell Research,2014,24(1):69-79.
[7]RINCHAI D,RIYAPA D,BUDDHISA S,et al.Macroautophagy is essential for killing of intracellular Burkholderia pseudomallei in human neutrophils[J].Autophagy,2015,11(5):748-755.
[8]LI W W,LI J,BAO J K.Microautophagy:lesser-known self-eating[J].Cell Mol Life Sci,2012,69(7):1125-1136.
[9]Cuervo A M,Wong E.Chaperone-mediated autophagy:roles in disease and aging[J].Cell Research,2014,24(1):92-104.
[10]MAZURE N M,POUYSSEGUR J.Hypoxia-induced autophagy:cell death or cell survival[J],Current Opinion in Cell Biology,2010,22(2):177-180.
[11]BELLOT G,GARCIA-MEDINA R,GOUNON P,et al.Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains[J].Mol Cell Biol,2009,29(10):2570-2581.
[12]ZHANG H,BOSCH-MARCE M,SHIMODA L A,et al.Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia[J].J Biol Chem,2008,283(16):10892-10903.
[13]CHOI K S,BAE M K,JEONG J W,et al.Hypoxia-induced angiogenesis during carcinogenesis[J].J Biochem Mol Biol,2003,36:120-127.
[14]FANG J S,GILLIES R D,GATENBY R A.Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression[J].Semin Cancer Biol,2008,18(5):330-337.
[15]SELVAKUMARAN M,AMARAVADI R K,VASILEVSKAYA I A,et al.Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy[J].Clin Cancer Res,2013,19(11):2995-3007.
[16]眭怡群,冯一中.自噬相关基因LC3、Beclin-1与凋亡相关基因p53、BCL-2在大肠癌中的表达及意义[J].临床与实验病理学杂志,2012,28(3):282-286.
[17]GIATROMANOLAKI A,KOUKOURAKIS M I,KOUTSOPOULOS A V,et al.Autophagy and Hypoxia in colonic adenomas related to aggressive features[J].Colorectal Dis,2013,15(5):223-230.
[18]ZHANG H,GAO P,FUKUDA R,et al.HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity[J].Cancer Cell,2007,11(5):407-420.
[19]WARBURG O.On the origin of cancer cells[J],Science,1956,123(3191):309-314.
[20]HANAHAN D,WEINBERG R A.Hallmarks of cancer:the next generation[J],Cell,2011,144(5):646-674.
[21]GAO J L,CHEN Y G.Natural compounds regulate glycolysis inhypoxic tumor microenvironment[J].Biomed Res Int,2015,2015:354143.
[22]侯晓莹,杜鸿志,袁胜涛.基于能量代谢的抗肿瘤药物研究进展[J].肿瘤防治研究,2017,4(3):231-235.
[23]HSU P P,SABATINI D M.Cancer cell metabolism:Warburg and beyond[J].Cell,2008,134(5):703-707.
[24]LEVINE B,KLIONSKY D J.Development by self-digestion:molecular mechanisms and biological functions of autophagy[J].Dev Cell,2004,6(4):463-477.
[25]JUNG C H,RO S H,CAO J,et al.mTOR regulation of autophagy[J].FEBS Lett,2010,584(7):1287-1295.
[26]LIN G,ANDREJEVA G,WONG TE FONG A C,et al.Reduced Warburg effect in cancer cells undergoing autophagy:steady-state 1 H-MRS and real-time hyperpolarized 13 C-MRS studies[J].Plos One,2014,9(3):e92645.
[27]LOCK R,ROY S,KENIFIC CM,et al.Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation[J].Mol Biol Cell,2011,22(2):165-178.
[28]GUO J Y,CHEN H Y,MATHEW R,et al.Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis[J].Genes Dev,2011,25(5):460-470.
[29]KIM S,KIM DO H,JUNG WH,et al.Metabolic phenotypes in triple-negative breast cancer[J].Tumour Biol,2013,34(3):1699-1712.
[30]黄贵华,纪云西,吴大力,等.细胞自噬与中医气虚痰瘀关系探讨[J].中医杂志,2011,52(20):1717-1719.
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[32]周俊亮.中医脾与线粒体关系探讨[J].辽宁中医杂志,2006,33(3):287.
[33]戎志斌,罗安明,姚乃礼.“脾虚-线粒体-有氧糖酵解-肿瘤关联”病因病机新假说[J].医学争鸣,2016,37(1):19-22.
[34]郑舞,杨金坤.肿瘤微环境及其中医病机[J].中医杂志,2015,56(20):1720-1723.
[35]徐文娟,孙学刚.论脾虚是结直肠癌能量代谢障碍与上皮间质转化的关键病机[J].中国中医基础医学杂志.2015,21(5):500-502.
[36]刘杉珊.5-Fu联合Wortmannin在wtp53/mtp53结肠癌细胞中的作用研究[D].长春:吉林大学,2011.
[37]孔娜.JNK介导的保护性自噬促进了p53～(-/-)或p53突变型结肠癌细胞对5-FU的耐药[D].杭州:浙江大学,2014.
[38]丁宁,杨宇飞,刘羿男,等.健脾活血解毒法拆方含药血清对人大肠癌细胞HCT-116细胞的增殖抑制作用及其机制研究[J].中国实验方剂学杂志,2013,19(11):272-275.
[39]张瑞娟,许建华,孙珏,等.肠胃清方对人结肠癌HCT116/L-OHP裸鼠皮下移植瘤miR-30a/Beclin1通路的影响[J].世界华人消化杂志,2017,25(12):1061-1070.