https://www.mdpi.com/2072-6694/12/3/562/htm
Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma
Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to va
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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.
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