자가포식: 간세포 암종에서 폴리페놀의 잠재적인 치료 표적

 

https://www.mdpi.com/2072-6694/12/3/562/htm

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

Table 1. Dysregulated autophagy genes/proteins in cancer.

Genes/               ProteinsFunction in Autophagy                Alterations in Cancer                           Reference

BECN1	Autophagosome formation	Monoallelic deletion of the Beclin-1-encoding gene in the human breast, ovarian, prostate, colorectal cancers, leukemia, lung, liver, endometrial, colorectal, glioblastoma and brain cancers	[93,94,95,103]
EI24/PIG8	Autophagosome formation and/or degradation	Mutations and deletions are associated with human early-onset breast cancers	[100]
mTOR	Autophagy regulation	Somatic mutation of mTOR in melanoma, lung (large cell), ovary (mucinous), colorectal, brain and kidney cancer cells	[104]
Atg5	Autophagic vesicle formation	Alterations of Atg5 protein expression and somatic mutations of the Atg5 gene are found in prostate cancers	[100,101]
Atg2B, Atg9B, Atg5 and Atg12	Implementation of the autophagy process; autophagosome formation in early stages autophagy	A frameshift mutation in gastric and colorectal cancers	[105]
UVRAG	Nucleation and fusion	Deletion mutation is associated with human colorectal cancer Mutated in gastric and colorectal cancers with microsatellite instability	[105,106]
p53	Autophagy regulation	Somatic mutation in human cancer	[107]
DRAM1	Autophagy regulation	Substitution mutation in human non-small cell lung carcinoma cell	[108]
LAMP2	Mediation of transport of a specific set of cytosolic proteins across the lysosomal membrane in chaperone-mediated autophagy	A missense mutation in pancreatic cancer	[109]
Parkin (E3 ubiquitin ligase)	Autophagy regulation via Bcl-2	A point mutation in ovarian, breast, bladder and lung cancer	[110]

Table 2. Autophagy-associated anti-HCC polyphenols.

PolyphenolsCompounds        Cancer Model(Cell line/Animal)         Role in Autophagy                           Reference

Flavonoids
Flavones	Apigenin	HepG2	Inhibited PI3K/Akt/mTOR pathway and downregulated SQSTM1	[176]
	Oroxylin A	HepG2	Caused overexpression of Atg5 and Atg7, inhibition of autophagy by si-Beclin-1 and 3-methyladenine and suppression of PI3K-PTEN-Akt-mTOR signaling pathway	[177]
	Isorhamnetin	Mice	Interfered with p38/PPAR-α pathway	[178]
	Baicalein	SMMC-7721	Displayed downregulation of CD147 and protective autophagy; Protective autophagy via ER stress	[180] [181] [195]
	Tangeretin	HepG2	Interfered with JNK/Bcl-2/Beclin-1 -mediated pathway	[182]
	Wogonin and sorafenib combination	Hep3B & Bel-7402, HepG2 & SMMC-7721	Induced autophagy inhibition	[183]
	Isoorientin	HepG2	Induced overexpression of Beclin-1 and LC3-II, ROS-related p53, PI3K/Akt, JNK, and p38	[184]
	Luteolin	SMMC-7721	Increased Beclin-1 expression and LC3B-II conversion	[185]
Flavonols	Galangin	HepG2 Hep3B	Interfered with p53-dependent pathway and TGF-β receptor/Smad signaling pathway	[186] [187]
	Kaempferol	SK-HEP-1 HepG2 & Huh 7	Increased protein expression of p-AMPK, LC3-II, Atg 5, Atg 7, Atg 12 and Beclin- 1 CHOP-autophagy mediated	[188] [189]
	Quercetin	LM3 Mice	Increased expression of LC3, and downregulated expression of p62; Activated autophagy, Increased the formation of autophagosomes and autolysosomes	[190] [191]
	Myricetin		Inhibited the phosphorylation of mTOR	[192]
Flavanols	EGCG	HepG2	Increased expression of Beclin1, Atg5, increased level of p62 autophagic substrate, promoted the synthesis of LC3-II	[193] [196]
	EGCG and doxorubicin combination	Hep3B	Increased Beclin-1 and Atg5 expression and suppressed LC3 expression	[194]
Anthocyanidins	Delphinidin	SMMC-7721	Exhibited overexpression of LC3-II	[197]
Non-flavonoids
Stilbenes	Resveratrol	Huh 7 MHCC-97H	Increased the expression of autophagy-related proteins Atg5, Atg7, Atg9, and Atg12 Activated p53 and inhibited PI3K/Akt	[198] [199]
Hydroxycinnamates	EHHM	HepG2	Increased the expression of Atg5, Beclin-1 and LC3-II proteins	[200]
Miscellaneous non-flavonoids	Curcumin	Huh 7 HepG2	Increased the formation of autophagic vacuoles due to the conversion of LC3-I to LC3-II; Induced autophagy with decreased expression of SQSTM1	[201] [202]
	Curcumin with adriamycin (doxorubicin)	HepG2	Increased the expression of LC3-II protein	[203]
Analogs of non-flavonoids	EF25-(GSH)2	HL-7702	Induced autophagy	[204]
	WZ35	HCCLM3	Downregulated YAP-mediated and autophagy inhibition	[205]

그림 3. 자가포식 유발 항HCC 폴리페놀 신호 전달 경로의 개략도. 

 

간암에 대한 플라보노이드에 의해 매개되는 자가포식 관련 신호전달 메커니즘. 

Apigenin, oroxylin A 및 resveratrol은 PI3K/Akt/mTOR 신호 전달 경로를 억제할 수 있습니다. 

루테올린, 이소오리엔틴, 케르세틴, 캠페롤, 커큐민, 커큐민, 아드리아마이신 포함, EGCG, EHHM, 델피니딘, EF25-(GSH) 2LC3 II의 전환에 관여하면 자가포식을 유도할 수 있습니다. 

미리세틴은 mTOR 신호 전달 경로의 인산화를 억제할 수 있습니다. 

Oroxylin A, resveratrol 및 kaempferols는 autophagy 관련 단백질을 증가시켜 LC3 II의 지질화를 증가시킬 수 있습니다. 

소라페닙, WZ35 및 탄게레틴과 함께 Wogonin은 자가포식 경로를 억제할 수 있습니다. 

Galangin은 TGF-β 수용체/Smad 신호 전달 경로에 의해 자가포식을 유도할 수 있습니다. 

바이칼레인은 CD147의 음성 조절과 연관되어 ER 스트레스를 통해 보호 자가포식을 매개할 수 있습니다.