This document summarizes the role of reactive oxygen species (ROS) in activating apoptosis and autophagy in cancer cells. It discusses how ROS are generated endogenously and exogenously, and how cells have antioxidant systems to maintain homeostasis. At high concentrations, ROS can induce apoptosis through both intrinsic and extrinsic pathways by modulating proteins like caspases, Bax, and Bcl-2. ROS have also been shown to induce autophagy by activating proteins involved in autophagosome formation like ATG4, Beclin-1, and modulating signaling pathways such as AMPK/mTOR. Many chemotherapy drugs and natural compounds exert their anticancer effects at least partially through increasing ROS levels and
Lipocalin 2 as a Potential Diagnostic and/or Prognostic Biomarker in Prostate...
Reactive Oxygen Species (ROS) an Activator of Apoptosis and Autophagy
1. Kashyap et al. 2016 Scienceindoors Publishers
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256-264
Tapan K. Mukherjee3
1
Department of Histopathology,
Postgraduate Institute of Medical Education
and Research (PGIMER), Chandigarh,
Punjab, India-160012.
2
Department of Chemistry, Career Point
University, Tikker-Kharwarian, Hamirpur,
Himachal Pradesh 176041, India.
3
Department of Biotechnology,
M.M. University, Mulana, Ambala, Haryana, India.
4
Department of Biochemistry, Delhi University,
South-Campus, New Delhi, India.
5
Department of Chemistry, MM University,
Sadopur, India.
*Corresponded author:
Dr. Hardeep Singh Tuli, Assistant Professor,
M.M. University, Mulana, Ambala, Haryana, India.
Email: hardeep.biotech@gmail.com
Received: November 6, 2016
Accepted: December 2, 2016
Introduction
Reactive oxygen species (ROS) are the oxygen
containing species like O2-
, OH−
with free unpaired
electrons which make them highly energetic and
reactive. Their formation and elimination in the
healthy cells is constant, which is obligatory for the
well-functioning of many biological processes [1].
These species are generated by the different modes
such as by mitochondria-dependent manner, NADPH
oxidase, cytokines, growth factors (HGF and TGF-β),
and tumor promoters (12-O-tetradecanoylphorbol-13-
acetate or TPA) [2]. The leaking of electrons from
complex III of mitochondrial electron transport chain
during the respiration, also increase the production of
ROS. A particular concentration of generating ROS
plays crucial role in different cancer process. At high
concentration they activate oxidative stress, apoptosis
which leads to cell death, on contrast their low
concentration activate the angiogenesis and initiate
invasion and metastasis of tumor cells [3, 4].
Generated ROS cause damage to the tissues in various
forms, including induction of oxidative stress which
causes cardiovascular disease, neuro-degeneration and
leads to carcinogenesis by causing damage to DNA,
lipids, and cellular proteins [5]. ROSs are important
inhibitors of cancer cell proliferation via apoptosis
inducer. Elevated production of ROS in cancer cells
induces apoptosis or autophagy [6]. Most of the
treatment therapies for cancer include the elevation of
ROS by antioxidant system suppression in the cancer
cells to target the self-renewal of cancer stem cells
(CSC), epithelial-mesenchymal transition (EMT), and
angiogenesis [7-9]. Several studies support the
phenomenon of NADPH blockage or inhibition in the
tumor cell that help tumor cell to evade elevated ROS,
which could be reverse as an anti-tumor approach [2].
The present review article is subjected to
comprehensively describe associations of ROS with
cancer processes like apoptosis, autophagy and their
potential implication in the development of novel anti-
cancer drugs.
Role of reactive oxygen species in apoptosis
Apoptosis, a programmed cell death having two well
defined intrinsic and extrinsic pathways, is required
for tissue morphogenesis during early embryonic
development [10–12]. Intrinsic and extrinsic pathways
of apoptosis involve the mitochondrial membrane
disruption which releases Cyt-c in the cytoplasm,
activates caspase-9, 3 and induce FAS receptor and
caspase 8 respectively [13-19]. It has been
demonstrated that ROS generation induces both the
apoptotic pathways by regulation caspase cascade and
activating Fas and ERK 1/2 and p38 MAPK signaling
Scienceindoors Publishers
Journal of Biological and
Chemical Sciences
Review article
Reactive Oxygen Species (ROS): an Activator of Apoptosis and Autophagy
in Cancer
Abstract
Despite significant improvements in the technical aspects of cancer diagnosis and
management, it is still a leading cause of mortality worldwide. Although, the development
of a variety of therapeutic strategies with effective mechanisms of action is increasing, the
advanced understanding of molecular mechanisms of cancer initiation and progression is
still the important consequence. Reactive oxygen species (ROS) with great concern due to
the ability to modulate cell survival and cell death signaling pathways are could be
considered to design the effective anti-cancer strategies. Several anti-cancer agents used
for the treatment of various cancers regulates ROSs generation which subsequently
modulate the pro-apoptotic molecules, expression of various transcription factors
including Sp1, AP1, NF-kβ, and other pro-oncogenic genes that are engaged in cancer cell
proliferation, survival and metastasis. Concentration dependent ROS has distinct role in
different cancer processes like in apoptosis, cancer survival, autophagy, angiogenesis,
metastasis, and inflammation. Radiation and potent agents used in chemotherapy are
working on the phenomenon of ROS generation that inhibit cancer process. With the
intense understanding of ROS’s role in the particular cancer process which is inevitable in
cancer, may be used in health care to improve patient’s survival rate. The current review
presents all the proposed molecular interactions of ROS with their known cellular targets
in cancer cell.
Dharambir Kashyap1
, Ajay Sharma2
, Vivek kumar Garg1
, Hardeep Singh Tuli3*
, Gaurav Kumar4
, Manoj Kumar5
2. Kashyap et al. 2016 Scienceindoors Publishers
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256-264
pathways [6, 20–25]. Several studies done so far
demonstrated the ROS-mediated apoptosis activation
as a consequence of loss of mitochondrial membrane
potential, release of Cyt-c, activation of caspase 9, 3,
cleavage of PARP and down-regulation of Bcl2 and
up-regulation of pro-apoptotic protein Bax in LLC-
PK1, A2058, A375, and A875 cells [26–28]. An in-
vitro study with melanoma cells revealed the
involvement of Akt and p38 MAPK pathway in ROS-
mediated apoptosis [29-30]. Similarly, study using
natural product as a potent anticancer molecule
determined the ROS-mediated activation of ERK,
JNK, and p38 MAPK leading to the activation of
caspase-3 in Gastric cancer BGC-823 cells and
multiple myeloma U266 cells [31-32]. Moreover,
ROS-mediated apoptosis was also observed in CML-
T1 leukemia cells and peripheral blood lymphocytes
[33]. Additionally, Keswani et al., 2014 noticed ROS-
dependent apoptosis in Palladium(II) complex-treated
A-549 lung cancer cells [34]. Recently, Yao et al.,
2015 reported 23-hydroxybetulinic acid derivative
B4G2-induced depolarized mitochondrial membrane
potential, released Cyt-c, activated caspase-9 and
caspase-3 and cleaved poly ADP-ribose polymerase
(PARP), and increased concentration of intracellular
Ca2+
and ROS which activated the apoptosis in the
liver cancer cells [35]. In addition, Dixit et al., 2014
suggested ROS-mediated apoptosis in glioma cells as
a consequence of Yes-associated protein 1 (YAP1),
ATM and JNK activation [36]. Moreover, ROS-
mediated endoplasmic reticulum (ER) stress was
additionally found to be associated with apoptosis
initiation in carnosic acid-treated human renal
carcinoma Caki cells [37]. In another study using head
and neck carcinoma, the anticancer agent
dihydromyricetin (DHM) leads which increases p-
STAT3-dependent apoptosis by ROS generating
signaling pathways has noticed [38]. Tideglusib
another anticancer molecule has been reported to be a
dose dependent activator of pro-apoptotic proteins
(PARP, Caspase-9, Caspase-7, Caspase-3) and tumor-
related genes (FasL, TNF-α, Cox-2, IL-8, Caspase-3)
in human neuroblastoma IMR32 cells through the
generation of ROS [39]. In human epithelial ovarian
cancer cell lines OAW42 and OVCAR3 apoptosis
induction was correlated with increased ROS
generation under the effect of cocoa procyanidin [40].
Su et al., 2016 also indicated the apoptotic effect of
carnosoic acid in in-vitro as well as in-vivo cervical
cancer model via promoting ROS and activating JNK
Figure 1: Endogenously, increased metabolic activity, peroxisome activity, increased cellular receptor signaling, oncogene activity,
cyclooxygenases, lipoxygenases, thymidine phosphorylase, endoplasmic reticulum (ER) system, and NADPH oxidase (NOX) complex, and
exogenously ultraviolet radiation (UVR), ionizing radiation (IR) and hypoxia are the prominent factors for ROS generation. To counter the
production of these ROS inducers, cells possess their scavenger systems in the forms of SOD, catalase, and Gpx to maintain the homeostasis.
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signaling pathways [41]. Thus, great evidence
supporting and suggesting the phenomenon of ROS
mediating apoptotic cell death which could be an
effective treatment approach for cancer cure.
Role of reactive oxygen species in autophagy
Autophagy is an evolutionarily conserved catabolic
process which involves degradation of cellular
components such as proteins and organelles in
lysosomes and serve as an alternative source of energy
during metabolic stress to maintain cellular
homoeostasis and survival [42]. Considering its
crucial role in cell death, autophagy may be used as an
alternative and promising therapeutic target for cancer
in apoptosis-resistant malignancy [43-45]. Till date,
more than 34 types of different proteins and many
signaling pathways has identified and characterized
which could induce autophagy process [46–48].
Growing evidence has suggested the involvement of
ROSs in the modulation of various autophagy
regulating proteins such as ATG4, AMPK and NF-kβ
and in cancer inhibition [49, 50]. Various natural and
synthetic molecules are associated with the inhibit of
cancer proliferation through ROS-mediated autophagy
induction [51, 52]. BNIP3 (Bcl2 nineteen-kilodalton
interacting protein), a stress-induced protein has been
found to be up-regulated by ROS in a number of
cancers [53–58]. Autophagy-cognate gene (Atg4) is
another important autophagy triggering protein which
is activated byROS and consequently up-regulates the
expression of LC3-II which required to initiat an
autophagosome formation [59–61]. Zhang et al., 2008
investigated the role of hypoxia-induced
mitochondrial ROS in in-vitro and in-vivo model and
reported the activation of BNIP mediated Beclin-1 and
Atg5 which subsequently induced cell death [62, 63].
Investigating MCF-7 cells, Angela Alexander et al.,
determined that elevated ROS could induce autophagy
by activating ATM-mediated TSC2 tumor suppressor
gene via LKB1-AMPK-mTORC1 signaling pathway
[64]. In a study, using human osteosarcoma cell line
(MG63), Guang-rong Ji et al., 2015 noted the
involvement of PERK in stress-induced autophagy
through inhibition of mTOR pathway [65]. In recent
years, a number of chemotherapeutic and
phytochemicals agents have developed that are potent
modulators of ROS-mediated autophagy signaling
pathways [43, 66–72] For example, oleanoic acid
trigger the ROS generation in HepG2 and SMC7721
cells and activate the autophagy confirmed by
Figure 2: ROS generated by endogenously or exogenously means can activate both intrinsic and extrinsic apoptosis pathways. MAPK, Bax,
and Bcl2 cell signaling molecules modulation in response to the ROS activate the downstream caspase cascades which further resulted in
apoptotic cell death.
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increased distribution of LC3 and an increased ratio of
LC3-II to LC3-I in these cancer cell [73]. Similarly
Macranthoside B, has been known to induced the
autophagy mediated cancer cell death by modulating
the ROS/AMPK/mTOR pathway in A2780 human
ovarian carcinoma cell [74]. In addition, the studies
also identified the ROS-dependent activation of
autophagy in glioma cell and HepG2 cells by
modulation of PI3K/Akt and MAPK signaling
pathways [63, 75, 76]. Moreover, PLB a naturally
occurring naphthoquinone process the anti-cancer by
Sirt1 and PI3K/Akt/mTOR-mediated autophagy in
PC-3, DU145, and SCC25 cells [77, 78]. Further, L
Zhang et al. 2014 relevealed the autophagy induction
depending on suppression of the
PI3K/AKT/mTOR/p70S6K and activation of JNK
signaling pathways via ROS arbitrated after the
treatment of human glioblastoma cells by cathepsin-S
[79]. In the similar way, nimbolide, an active molecule
from Azadirachta indica, has been reported to exhibits
anti-proliferative properties mediated by ROS
generation that reduce PI3K/AKT/mTOR and ERK
signaling in pancreatic cancer [80].
Conclusion and future perspectives
ROS are considered to be essential cellular molecules
in order to maintain physiological homeostasis.
Evidence has suggested that low levels of ROS play a
significant role in cellular signaling by acting as a
secondary messenger, whereas at higher
concentrations ROS could act as potent anti-cancer
agents. Numerous chemotherapeutic drugs have been
found to induce cell death by activating ROS
generation [81–83]. Furthermore, in comparison to
non-transformed cells, cancer cells have been found to
have moderately elevated levels of both ROS as well
as antioxidant molecules [84, 85]. Therefore,
conventional ROS-mediated anticancer therapies may
fail in cancer cells due to abundant presence of
antioxidant molecules. Using compounds with
inhibitory effects on antioxidant enzymes could thus
play an important role in the ROS-mediated fight
against neoplasms opening new perspectives in cancer
research [86,87]. Therefore, to develop an efficient
anti-cancer treatment modality, the scientific
community should completely understand the redox
state of the tumor. This means that cellular
mechanisms involved in the production of ROS and
their downstream regulated molecular targets and
signaling pathways urgently need to be unraveled.
Acknowledgements
The authors fully acknowledge Department of
Histopathology, Postgraduate Institute of Medical
Education and Research (PGIMER), Chandigarh and
Maharishi Markandeshwar University, Mullana-
Ambala and for providing the requisite facility to carry
out the study.
Conflict of interest
The authors have declared no conflicts of interest.
Figure-3: ROS-mediated activation of autophagy by autophagosome formation is controlled by various factors including mTOR/Akt, AMPK,
VPS34, beclin 1, and PERK which has been known to be modulated by ROS generation.
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256-264
Ethical approval
This article does not contain any studies with human
participants or animals performed by any of the
authors.
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