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Nagayama. J Cancer Metastasis Treat 2021;7:6 I http://dx.doi.org/10.20517/2394-4722.2020.114 Page 11 of 16

increases cell death, and cell-survival effects of various autophagy inducers are abolished by autophagy
inhibitors as summarized in Table 1. However, there are indeed some exceptions for autophagy-inhibition
of apoptosis; for example, autophagy degrades pro-survival factor caveolin-1, activates caspase 8, and
[19]
plays a role as scaffolds for apoptosis execution . Furthermore, autophagy is reported to be a back-up
mechanism for death of cells defective in or resistant to apoptosis during development [100] , and in cancer
cells [101] . Therefore, the consequence of modulation of autophagic activity may be dependent on the
sensitivity/resistance of the cancer cells to apoptotic stimuli; apoptosis-resistant cells may be vulnerable to
[19]
autophagy inducers. Autophagy is also known to modulate other types of cell death which, however, have
never been studied in the thyroid cells.

The degree of dependency on or addiction to autophagy in cancer cells may determine response to
autophagy modulators [102] . Autophagy dependency is reportedly controlled by p53 status, RAS/RAF family
status, JAK/STAT/PI3K signaling pathways, and so on. In fact, BRAF V600E promotes autophagy dependence
in multiple tumors [37,102-104] , presumably as do RAS and RET/PTC. Thus, thyroid cancers, most of them have
mutant RAS/RAF or RET/PTC, likely depend on autophagy for their proliferation/survival.

There are also some lines of evidence supporting anti-survival/proliferative effect of autophagy. The
autophagic machinery executes specific forms of cell death, called “autophagic cell death” or “autophagy-
dependent cell death” [19,20,105] . The mechanisms include: (1) over-eating due to excessive-consumption of
cellular organelles and cytoplasmic contents; (2) excessive mitophagy leading depletion of mitochondria
+
+
and consequent energy failure; and (3) autosis by activation of Na /K ATPase pump and changes in
[73]
membrane osmolarity and ion transporter. In this regard, it may be worth noting here that Li et al.
mentioned that “although sustained and profound autophagy activation could promote cell death
(autophagic cell death), drug-induced feedback autophagy activation is mostly gentle and has pro-survival
ability especially in cancer cells”. It is also of interest that rosuvastatin (a statin) induced autophagy at lower
concentrations, which shifted to apoptosis with higher concentrations, in BCPAP cells [106] . More recently,
dendrogenin A (DDA), which is a cholesterol-derived metabolite and a ligand of the liver X receptor and
is reported to induce lethal autophagy in other cancer cells [107] , was demonstrated to induce cell death/
cell cycle arrest and re-differentiation in thyroid cancer cell lines, B-CPAP and 8505C, although the
consequence of autophagy inhibition from DDA is not evaluated [108] .

Autophagy also controls thyroid differentiation status. Thus, there is a significant association between LC3
puncta and RAI uptake capacity/solute carrier family 5 member 5 [SLC5A5, or sodium/iodine symporter
[54]
(NIS)] expression/clinical response to RAI . Experimentally, some of autophagy inducers (all are digitalis-
like compounds) increased RAI uptake in at least one of three PTC or FTC cell lines (BCPAP, TPC1, and
FTC133) and in both ATC lines (8505C and Cal-62) (NOTE - all the autophagy inducers examined did not
do so in all the cell lines examined, so that this effect may be attributed to their distinct intrinsic nature, not
their autophagy-inducing ability, of digitalis-like compounds and/or different cells used, and also whether
this effect is abolished by an autophagy inhibitor or not should be addressed.) [109,110] .

Keeping all these possibilities in mind (summarized in Figure 3), although currently researchers mainly
focus on autophagy inhibitors as a therapeutic modality for thyroid cancer, excess autophagy should also be
considered as another choice.

Finally, of interest, intra-nuclear cytoplasmic inclusion, known as one of the diagnostic criteria for PTCs,
is recently reported to be formed by nuclear invagination and contain autophagy-related proteins such as
LC3, p62, ubiquitin, and cathepsin B/D, and also BRAF V600E[111] , although its clinical significance remains to
be elucidated.