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Monks et al. J Cancer Metastasis Treat 2019;5:24 I http://dx.doi.org/10.20517/2394-4722.2018.79 Page 9 of 23

One of the mechanisms by which APN prevents cancer growth is by promoting apoptosis via cytotoxic
autophagy. A recent study using BC cells demonstrated that APN induces an accumulation and fusion of
autophagosomes and lysosomes which leads to apoptosis. Central to this pathway is the AMPK mediated
activation of the ULK1 (Unc-51 like autophagy activating kinase 1) axis which is regulated by upstream
STK11/LKB1 (serine/threonine kinase 11/Liver kinase B1) [119] . Autophagy can be cytoprotective, cytotoxic,
cytostatic, or non-protective. Due to the cytoprotective role of autophagy many studies have looked to see
whether inhibition of autophagy can be used in combination with chemotherapy to increase sensitivity
to therapy [120] . In contrast, this study has shown that by stimulating cytotoxic-autophagy it can enhance
efficacy of chemotherapy. The dual role of autophagy in tumour suppression and promotion makes utilising
this pathway therapeutically challenging and more studies are needed to determine how APN induced
autophagy can be used in combination with other treatments.

The intracellular accumulation of ceramides have been associated with pathogenesis such as insulin
resistance and endothelial dysfunction [121,122] . Activation of ceramidase enhances ceramide catabolism to the
anti-apoptotic sphingosine-1-phosphate [123] . A recent study showed that APN signalling through T-cadherin,
but not AdipoR1/R2, reduced cellular ceramide by enhancing exosome biogenesis and secretion [124] . This is
a novel mechanism by which APN can lower intracellular ceramide and prevent cellular damage. Unlike
AdipoR1/R2, T-cadherin is usually downregulated in cancer cells and re-expression of the receptor has been
associated with a better prognosis [125] . Despite APNs anti-oncogenic pathways, dominance of the ceramidase
pathway may enable over expression of AdipoR1/R2 to be pro- rather than anti-oncogenic. When assessing
the overall effect of APN, it is important to consider the time at which AdipoR1/R2 are overexpressed in
cancer, the concentration of serum APN, and which isoform is circulating.

INDIRECT EFFECT OF APN PATHWAY ON ANTI-CANCER IMMUNITY
Chronic inflammation in adipose tissue, mediated by adipokine signalling, and immune system dysfunction
hold important roles in cancer initiation [126] . APN has been shown to have anti-inflammatory properties
through interaction with the innate and adaptive immune system [Table 2]. The majority of this is mediated
by antigen-presenting cells (APC) of the innate immune system that produce anti-inflammatory cytokines
and inhibit pro-inflammatory cytokines. That said, APN has also been shown to have pro-inflammatory
effects [Table 2], suggesting that there may be situations where APNs effects shift from anti- to pro-
inflammatory.

One of the central anti-inflammatory cytokines APN induces is IL-10 [Table 2]. The mechanism of IL-10
transcription from APN may be mediated through several pathways. One known pathway is that gAcrp
exposure leads to AMPK and ERK1/2 mediated CREB transcription of IL-10 [129] . Multiple studies have
demonstrated that gAcrp is the best inducer of IL-10. However, one study showed that activation of AdipoR1
by either gAcrp or flAcrp can upregulate IL-10 through the AMPK and MAPKp38 pathway [Figure 3]. IL-10 has
a multitude of anti-inflammatory effects [164] , one of these may be exerted through activation of the STAT3/
suppressor of cytokine signalling (SOC3) pathway. Activation of the IL-10 receptor activates this pathway
which leads to downstream inhibition of NF-κB [Figure 3].

Although APN levels are generally negatively correlated with cancer risk, high expression of the APN
receptors has equally been correlated with tumour progression. Activation of upregulated AdipoR1 and
AdipoR2 on dendritic cells (DC) results in the arrest of DCs in an immature state and development of
tolerance to tumour antigens [117] . Each APN receptor has a separate pathway leading to inhibition of the
NF-κB pathway thought to induce DC tolerance [Figure 3]. That said, suppression of the NF-κB pathway
is a central anti-inflammatory mechanism that APN utilises [Table 3]. Activation of AdipoR1 results in a
IL-10 dependent activation of the STAT3/SOC3 pathway and inhibition of the NF-κB pathway. A STAT3-
knockout-DC study demonstrated that STAT3 is essential in developing the IL-10 dependent tolerance [165] .