Page 919 - Read Online

Ho et al. J Cancer Metastasis Treat 2019;5:70 I http://dx.doi.org/10.20517/2394-4722.2019.25 Page 7 of 20

alleviate proteotoxic stress and promote MM survival by (1) limiting the secretion of immunoglobulins
and (2) providing an alternative proteolytic pathway for the clearance of ubiquitinated proteins through
[60]
a p62-dependent mechanism . Despite this, concomitant inhibition of the proteasome and autophagy in
[60]
pre-clinical studies have reported inconsistent results, ranging from synergism to antagonism . This may
partly be explained by the observation that while basal autophagy is protective, persistent and uncontrolled
autophagy results in autophagic cell death [67,68] . Autophagic cell death in MM can be induced by caspase-10
or caspase-8 inhibition [67,68] . Specifically, caspase-10 cleaves and inhibits BCL2 associated transcription
factor 1, a BECLIN-1 activator, to temper the autophagic response and avoid cell death . MM cells
[67]
therefore need to tightly regulate autophagy to maintain viability as dysregulation either way leads to
deleterious effects in MM.

Mitophagy has been reported to play conflicting roles in carcinogenesis, survival, and drug-resistance.
Some studies report that mitophagy protects untransformed cells from excessive reactive oxidative species
damage and genetic instability, and that suppression of mitophagy favors carcinogenesis [69,70] . Conversely,
other studies suggest that mitophagy promotes cancer cell survival and drug resistance by protecting cells
from apoptosis [71,72] . In MM, while the suppression of mitophagy is associated with bortezomib resistance;
[73]
doxorubicin, a widely used anti-MM chemotherapy, is a classical inhibitor of mitophagy . This dichotomy
highlights the need for a better understanding of the role mitophagy plays in MM.

DNA damage and autophagy
Apart from ongoing proteotoxic stress, other hallmarks of MM are genetic instability and abnormalities
(e.g., aneuploidy, translocations), and oxidative stress which lead to replicative stress and constitutive
DNA damage [74,75] . Recent studies have shown that DNA damage can activate autophagy through a
[76]
number of interconnected pathways . Examples of DNA damage repair (DDR) pathway proteins that
regulate autophagy are ataxia telangiectasia-mutated (ATM), poly (ADP-ribose) polymerase 1 (PARP1),
c-Jun N-terminal kinase (JNK), and p53 . Specifically, autophagy can be induced by ATM-mediated
[76]
phosphorylation of AMP-activated protein kinase (AMPK) [77,78] . AMPK in turn activates both tuberous
sclerosis complex 2 (TSC2), to remove the inhibitory effect of MTOR complex 1 (mTORC1) on autophagy,
and unc-51 like autophagy activating kinase 1 (ULK1) to promote autophagosome formation [77-79] . ATM
also phosphorylates and activates CHE-1 which in turn upregulates the transcription of two mTOR
inhibitor genes [regulated in development and DNA damage responses 1 (REDD1) and DEP domain-
[80]
containing mTOR-interacting protein (DEPTOR)] . Nuclear factor-kappa B, a well-known pro-myeloma
[81]
transcription factor, can be activated by ATM and as a result, upregulate BECLIN-1 . Induction of PARP1
[82]
promotes autophagy via AMPK activation on the background of ATP depletion and elevated AMP levels .
DNA damage-induced JNK phosphorylates BCL-2 resulting in BCL-2 dissociation, relief of BECLIN-1
inhibition, and induction of autophagy . Nuclear p53 activates autophagy through a number of distinct
[83]
signaling pathways. Firstly, p53 upregulates phosphatase and tensin homolog (PTEN) which leads to PI3K-
Akt-mTORC1 inhibition and autophagy induction [84,85] . Secondly, p53 influences AMPK activity (1) directly
through transcriptional upregulation, and (2) indirectly by activating Sestrin1 and Sestrin2 which in turn
activate AMPK [85,86] . Thirdly, death-associated protein kinase (DAPK) is transcriptionally upregulated by
p53 and triggers autophagy by phosphorylating BECLIN-1 to facilitate its dissociation from BCL-2 and
BCL-X L [87-89] . DAPK also phosphorylates protein kinase D which activates the VPS34 class III PI3K
complex leading to induction of autophagy [87-89] . Lastly, p53 also upregulates damage-regulated autophagy
[90]
modulator, a lysosomal protein involved in the degradation step of autophagy . However, unlike nuclear
[91]
p53, cytoplasmic p53 can also activate mTOR to inhibit autophagy . Functionally, autophagy is essential
for homologous recombination and nucleotide excision repair and cells deficient in autophagy rely chiefly
on the error-prone non-homologous end joining repair pathway, which may explain the genomic instability
observed in autophagy-deficient cells [92-98] .