Natural agents mediated autophagic signal networks in cancer
Sohn and Park Cancer Cell Int
Natural agents mediated autophagic signal networks in cancer
Eun Jung Sohn 0 1
Hwan Tae Park 0
0 Peripheral Neuropathy Research Center, Department of Physiology, College of Medicine, Dong-A University , Dongdaesin-Dong, Seo-Gu, Busan 602-714 , Republic of Korea
1 College of Korean Medicine, Kyung Hee University , 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701 , Republic of Korea
Recent studies suggested that natural compounds are important in finding targets for cancer treatments. Autophagy (“self-eating”) plays important roles in multiple diseases and acts as a tumor suppressor in cancer. Here, we examined the molecular mechanism by which natural agents regulate autophagic signals. Understanding the relationship between natural agents and cellular autophagy may provide more information for cancer diagnosis and chemoprevention.
Autophagy; MicroRNA; Natural agents
Autophagy, also called type II programmed cell death,
is a catabolic process that leads to degradation of
targeted organelles or cellular proteins. The first stage of the
autophagic process is the formation of autophagosomes
arising from intracellular membrane structures, such as
the endoplasmic reticulum (ER), plasma membrane [
], Golgi or endosome , and the ER‒mitochondrial
contact site called the mitochondrion-associated ER
The serine/threonine protein kinase target of rapamycin
(TOR) acts as a central inhibitor of autophagy. In yeast,
TOR inhibition mediates the kinase activity of
autophagyrelated gene (Atg) 1 and enhances the Atg1 binding
affinity to Atg13 and Atg17 to initiate autophagosome
]. The mammalian Atg13/focal adhesion kinase
(FAK) family interacting protein of 200 kD (FIP200)/
UNC-51-like kinase complex mediates mechanistic
target of rapamycin (mTOR)-mediated autophagy
]. Multiple Atg proteins are required to form the
phagophore in autophagosome formation. To initiate the
phagophore, the membrane recruits PtdIns3K vacuolar
protein sorting 34, the myristoylated serine/threonine
kinase Vps15 (p150), Beclin 1, and Atg14 [
]. Next, the
elongation and expansion stages require a ubiquitin-like
system such as the ATG5/ATG12/ATG16L multimeric
complex and microtubule-associated protein light chain 3
(LC3) processing [
]. Finally, when the autophagosome is
mature, it fuses with the lysosome to form the
‘autolysosome’ to degrade organelles or cellular proteins.
Autophagy plays a role in several biological processes,
such as aging, development, and differentiation [
and it is regulated by 5′ AMP-activated protein kinase
(AMPK) and mTOR downstream of PI3 kinase/AKT,
which control cell growth and protein synthesis .
When growth factors are withdrawn, the autophagosome
forms to induce autophagy [
Autophagy and cancer: anti‑tumorigenic effects of autophagy
Autophagy is both inhibitory and beneficial to
malignant transformation [
]. Mukubou et al. showed
that enhanced sensitivity of pancreatic cancer cells to
gemcitabine or ionizing radiation treatment activated
autophagic flux . Interference in the autophagic
machinery in heterozygous or homozygous knockout
mouse models resulted in oncogenesis [
]. Beclin 1,
which regulates the initiation stages of autophagosome
formation, plays a role as a tumor suppressor. Beclin
1−/− mice displayed tumorigenesis and altered early
embryonic development [
]. Beclin 1+/− immortalized
baby mouse kidney (iBMK) epithelial cells promoted
There is evidence that disruption of Atgs promotes
tumor cell death induced by anti-cancer drugs, such
as histone deacetylase inhibitors, temozolomide, and
]. Guo et al. showed that Atg7-deficient
lung tumors with p53 deletion resulted in lipid
accumulation . Pyo et al. [
] reported that Atg5 regulates
interferon-γ-induced autophagic cell death by interacting
with Fas-associated protein with death domain, which is
a key signaling molecule involved in cell death.
Autophagy and cancer: pro‑tumorigenic effects of autophagy
Autophagy is constitutively activated in cancer cells,
especially RAS-driven tumor cells [
transcriptional control of autophagy- and lysosome-related genes
induces pancreatic cancer metabolism . Wei et al.
] demonstrated that deletion of FIP200, which plays
a role in autophagy, inhibits mammary tumorigenesis
by impairing tumor cell proliferation in vivo in an
oncogene-driven tumor model. There are several reports that
accumulation of p62, which is a marker of autophagic
flux, affects tumorigenesis and/or tumor progression.
For instance, expression of p62 is highly induced in
nonsmall-cell lung cancer [
] and breast cancer [
p62/SQSTM1-knockout mice showed inhibition of
RASinduced tumorigenesis compared with wild-type animals
Autophagy and apoptosis
Beclin 1/Atg six is an essential component involved in
formation of autophagic vesicles [
]. As shown in Fig. 1,
Beclin 1 interacts with Bcl-2, which is an anti-apoptotic
], and inhibits autophagy. The interaction
between Beclin 1 and Bcl-2 is via a BH3 domain in Beclin
], and interference of this interaction was found
to enhance autophagy [
There is evidence that caspases play important roles in
autophagy and apoptosis [
]. Oral et al. [
that caspase-8 overexpression resulted in Atg3 cleavage
and thereby its degradation. Caspase 9 interacts with
Atg7, and Caspase9–Atg7 complexes enhanced LC3II
]. Zhu et al. [
] reported that caspase-3 plays
an important role in autophagy via cleavage of Beclin-1
at positions 124 and 149. Therefore, crosstalk between
autophagy and apoptosis may provide important
information for cancer therapy.
Natural agents as modulators of autophagic signals
Several studies have revealed the therapeutic
effectiveness of drug re-positioning of existing drugs and the use
of newly developed drugs for the treatment of disease and
]. Natural agents have emerged as novel
Fig. 1 The scheme of Beclin 1 and Bcl2 interaction. Beclin 1 forms a
protein complex with VPS34. When Beclin 1 interacts with Bcl-2,
Beclin1–Bcl-2 complex inhibits autophagy. However, when Beclin1–Bcl-2
complex dissociate, autophagy initiates
therapeutic agents of drug-repositioning to influence
autophagic activity [
]. As shown in Fig. 2, several natural
agents modulate autophagy. For example, tanshinone IIA
], ursolic acid [
], quercerin [
], fisetin [
], and honokiol [
] act as inhibitors of the AKT/
mTOR pathway. Tanshinone IIA modulates the initiation
of phagophore formation. Ginsensoside [
] and ursolic
] affect the formation of autophagosomes.
Ginsenoside RO inhibits autophagosome–lysosome fusion
Resveratrol, a polyphenol phytoalexin found in grapes,
possesses anti-cancer [
] and antioxidant
functions . Resveratrol induced apoptosis and autophagy
in ovarian cancer cells via inactivation of signal
transducer and activator of transcription signaling [
induced autophagic cell death in prostate cancer cells
via regulation of stromal interaction molecule 1 [
It also induced autophagy via downregulation of the
Wnt/β-catenin signaling pathway in breast cancer
stem-like cells [
]. Ge et al. [
] reported that
resveratrol induced autophagy and apoptosis via repression of
AKT/mTOR/p70S6K/4E-BP1 and enhancement of p38
MAPK signaling in T cell acute lymphoblastic leukemia
Apigenin (4′,5,7-trihydroxyflavone), a naturally occurring
flavone found in many fruits (apples, grapes), vegetables
(onions, parsley), and tea, was shown to have
chemopreventive effects in vitro and in vivo [
]. Lee et al.
 showed that apigenin induced autophagy in HCT116
human colon cancer cells, and when combined with
3MA, which inhibits autophagy, it increased
apigenininduced apoptosis in HCT116 cells. Autophagy
inhibition enhanced apigenin-induced apoptosis in breast
cancer T47D cells [
]. Apigenin induced autophagic cell
death via reactive oxygen species (ROS) production and
accumulation of G2/M cell cycle arrest in human
papillary thyroid carcinoma cells [
Formation of autophagosome
Ursolic acid, a pentacyclic triterpenoid known for
its anti-tumor effects [
], increased the
expression of LC3-II, an autophagosome marker, and induced
autophagy via the Beclin-1 and AKT/mTOR pathways.
In addition, treatment with 3-methyladeninet or
Beclin-1/Atg5 siRNAs enhanced ursolic acid-mediated cell
cytotoxicity in prostate cancer cells . Xavier et al.
] reported that ursolic acid induced accumulation of
both LC3-II and p62 by activation of JNK in HCT15 cells.
Zhao et al. [
] demonstrated that ursolic acid treatment
induced autophagy via eukaryotic translation initiation
factor 2-α kinase 3 activity, implying that ER stress is
an important factor in autophagy. Leng et al. also
demonstrated that ursolic acid treatment led to apoptosis in
cervical cancer TC-1 cells and, according to
transmission electron microscopy, resulted in autophagic
vacuoles. siRNA-mediated knockdown of Atg5 combined
with ursolic acid treatment in TC-1 tumor cells
attenuated LC3 II accumulation, as shown by Western blotting,
implying that the ursolic acid-induced autophagy relies
on Atg5 [
Tanshinones (tanshinone I and IIA) are derived from
a traditional Chinese herb and are well-known
bioactive herbal compounds with chemopreventive
]. Tanshinone IIA activated LC3 II expression in
various cancer cells, such as prostate and gastric cells
]. It also induced apoptosis and autophagy via
the mTOR/p70S6K/AMPK pathway in KBM-5 leukemia
cells . Gao et al. [
] reported that treatment of 95D
cells with total tanshinones upregulated the expression
of autophagic proteins, such as Atg3, Atg5, Atg7, Atg12,
Beclin-1, and LC3II, in a dose-dependent manner. Jing
et al. demonstrated that tanshinone treatment of
gastric cancer cells, such as BGC823 and SGC7901 cells,
induced autophagy and attenuated tumor proliferation in
nude mice bearing BGC823 tumor xenografts [
Tanshinone II treatment in human osteosarcoma MG63 cells
upregulated Beclin, which is involved in the formation of
autophagic vesicles, inducing autophagy and apoptosis
via ROS [
Curcumin, a hydrophobic polyphenol, possesses
anticancer functions in various human cancer cells, such
as pancreatic and prostate cancer cells [
et al.  reported that curcumin treatment of colon
cancer HCT116 cells induces autophagy via inhibition
of the AKT/mTOR signaling pathway and
upregulation of the transcriptional activity of the transcription
factor EB. Guan et al. [
] also demonstrated that
curcumin treatment induced autophagy via activation of
AMPK and suppressed the proliferation and
migration of MDA-MB-231 breast cancer cells. Curcumin
induced autophagy by upregulating the AMPK pathway
in A549 lung adenocarcinoma cells as well [
et al. [
] showed that curcumin treatment induced
autophagy and suppressed invasion and proliferation in
human melanoma cells via inhibition of the AKT/mTOR
Kim et al. reported that ginsenoside Rg3 treatment of
hepatocellular carcinoma, using a GFP-mRFP-LC3
construct, suppressed autophagic flux. Combined treatment
with doxorubicin and ginsenoside Rg3 sensitized cells to
death via inhibition of autophagic flux [
20(S)-Rg3 treatment of ovarian cancer cells inhibited
cell growth and invasion while upregulating autophagic
related molecules, such as LC3II, ATG5, and ATG7.
Ginsenoside 20(S)-Rg3 treatment suppressed tumor growth
while upregulating LC3II, ATG5, and ATG7 levels [
Zheng et al. [
] showed that ginsenoside RO (RO)
treatment combined with chloroquine diphosphate did
not enhance LC3 II accumulation in esophageal cancer,
implying that RO inhibits autophagosome–lysosome
Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a flavonoid
present in fruits and vegetables [
] that possesses
], anti-inflammatory [
], and antioxidative
] actions. Suh et al. [
] showed that fisetin treatment
inhibited the growth of PC3Cap cells and induced LC3II
autophagic marker expression via inhibition of mTOR1/2
signaling. Klimaszewska-Wisniewska et al. observed that
combined treatment of fisetin and paclitaxel induced
autophagic cell death in A549 non-small-cell lung cancer
Treatment with oridonin, an active diterpenoid
compound isolated from Rabdosia rubescens, simultaneously
induced apoptosis and autophagy via ROS in HeLa cells
] and human multiple myeloma RPMI8266 cells [
Oridonin induced apoptosis and autophagy in human
prostate cancer cells [
]. Treatment with the nitric
oxide (NO) scavenger DTT and interruption of ERK and
p53 activation by PD98059, pifithrin-α, or ERK siRNA
decreased oridonin-induced apoptosis and autophagy.
This indicates that NO/ERK/p53 inhibited
oridonininduced apoptosis and autophagy in L929 cells [
Piperlonguminine, from the long pepper (Piper longum),
possesses anti-tumor activity [
] and suppresses the
phosphorylation of AKT/mTOR, thereby upregulating
ROS levels in several cancer cells, such as 786-O, PC-3,
and MCF-7 cell lines [
autophagy depends on ROS activation [
]. Xiong et al.
] also reported that piperlonguminine significantly
induced apoptotic molecules such as Bax, Bcl-2, and
caspase-3, autophagic markers such as Beclin-1 and LC3B,
phosphorylation of p38 and JNK, and ROS levels in bone
marrow mononuclear cells from patients with myeloid
leukemia. Piperlonguminine activated p38 protein kinase
via ROS, and SB203580, a p38 inhibitor, inhibited
piperlonguminine-mediated autophagy [
2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop2-enyl-phenol), a small molecule polyphenol, induced
both autophagy and apoptosis via inhibition of the PI3K/
AKT/mTOR pathway in neuroblastoma cells [
et al. showed that honokiol treatment of human thyroid
cancer cells induced anti-tumorigenic effects in vitro
and in vivo. LC3-II activity, a marker of autophagy, was
increased by honokiol treatment in concentration- and
time-dependent manners in thyroid cancer cells [
Quercetin, a dietary antioxidant present in fruits and
vegetables, is a chemopreventive compound. Wang et al.
] reported that quercetin induced the appearance of
autophagic vacuoles and formation of acidic vesicular
organelles, with conversion of LC3-I to LC3-II via
modulation of AKT/mTOR and hypoxia-induced factor 1α
signaling in gastric cancer cells.
Treatment with gingerol, which has anti-cancer effects,
blocked autophagic flux, and gingerol combined with
TRAIL sensitized cell death by blocking autophagic flux
in A549 lung adenocarcinoma cells [
Glabridin, an isoflavone, induced autophagy and
apoptosis in Huh7 human liver cancer cells via activation of
JNK1/2. Autophagy inhibitors, such as wortmannin and
BafA1, enhanced glabridin-mediated apoptosis [
The induction of autophagy is regarded as a strategy for
cancer prevention because of its function as a tumor
suppressor. Inhibition of the PI3K/AKT/mTOR signaling
pathway, which is dysregulated in human tumors, affects
autophagy. As shown in Fig. 2 and Table 1, natural agents
regulate various autophagic signals. Therefore, finding
natural agents that suppress PI3K/AKT/mTOR signaling
or induce autophagy may be a good strategy for cancer
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published maps and institutional affiliations.
AMPK: AMP-activated protein kinase; CQ: chloroquine diphosphate; ER:
endoplasmic reticulum; LC3: microtubule-associated protein light chain 3; mTOR:
mechanistic target of rapamycin; NSCLC: non-small-cell lung cancer; PI3K:
class III phosphatidylinositol 3-kinase; ROS: reactive oxygen species; STIM1:
stromal interaction molecule 1.
Conception and design, contribution of reagents, wrote the paper: EJS. HTP
designed and prepared the manuscript. Both authors read and approved the
The authors declare that they have no competing interests.
Availability of data and materials
All data is included in the manuscript.
Consent for publication
The authors consent for publication.
Ethical approval and consent to participate
This article does not contain any studies with human participants and animals
performed by any of the authors.
This was supported by the National Research Foundation of Korea (NRF)
Grant funded by Basic Research Program (2015R1C1A1A02036842 and
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