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Page 10 of 16 Nagayama. J Cancer Metastasis Treat 2021;7:6 I http://dx.doi.org/10.20517/2394-4722.2020.114
[58]
levels were determined in WB in the BANCR study . Tyrosine kinase inhibitors are recently approved
as a new thyroid cancer therapeutic regimen, especially RAI-refractory thyroid cancer. In this regard, the
relationship between tyrosine kinase inhibitors’ anti-cancer effect and autophagy is clinically of interest, but
the data on vemurafenib (CQ or 3-MA alone showed no cytotoxic effect but enhanced the vemurafenib’s
[68]
effect [70,76] ) and sorafenib (see the NOTE above ) are not consistent. More complicatedly, there is a report
that vemurafenib-induced autophagy is anti-survival in melanoma cells with BRAF V600E[84] that is otherwise
[83]
[70]
pro-survival in thyroid cancer cells as mentioned above .
(2) Studies reporting anti-survival/proliferative effect of autophagy on thyroid cancer
On the other hand, there are also some articles reporting the anti-survival/proliferative effects of
autophagy on thyroid cancers [Table 2], which include autophagy inhibitors of baculoviral IAP repeat
containing 7 (BIRC7) and miRNA-221/222 , and autophagy inducers such as natural compounds (e.g.,
[85]
[86]
[90]
[87]
[89]
[75]
[88]
sanguinarine , aloperine , allicin , mulberry anthocyanin , and apigenin ), long non-coding RNA
[91]
GAS8 antisense RNA1 (lncRNA GAS8-AS1) , doxorubicin , radiation , RAD001 (everolimus, an
[92]
[92]
[93]
[92]
[94]
mTOR inhibitor) , and Sirtuin 6 . NOTE - (1) although Lin et al. used doxorubicin as an autophagy
inducer because it increased LC3-II levels (p62 levels were not studied), it is shown in other papers that
doxorubicin blocks autophagy at the late stage (therefore increases both LC3-II and p62, like CQ) by
impairing lysosomal acidification [95-97] ; (2) the interpretation of the data on aloperine is difficult - alopeirne
increased both LC3-II and p62 levels but further increase in LC3-II could not be seen in combination
of aloperine and CQ indicating aloperine-inhibition of autophagy as mentioned earlier, while the red
fluorescence in aloperine-treated cells and yellow in aloperine and CQ-treated cells transfected with the
[88]
mRFP-EGFP-LC3 vector suggest aloperine-induction of autophagy ; and (3) the effect of anthocyanin
on autophagy was only studied by LC3-II levels in WB and formation of autophagosome by electron
microscopy and the GFP-LC3 vector but not by p62 levels or formation of autolysosome .
[90]
Inconsistent data between Tables 1 and 2 include (1) mTOR inhibitors CZ415 and RAD001 show the
[73]
opposite effects, pro-survival using TPC1 in the former and anti-survival using TPC1 and 8505C cells
in the latter ; and (2) radiation is also reported to be pro-survival in SW-579 cells and anti-survival in
[93]
[74]
[92]
TPC1 and 8505C cells .
(3) Studies reporting context-dependent effect of autophagy on thyroid cancer
The third group, context-dependent effect of autophagy on cell survival/proliferation, is also reported [Table 3].
Thus, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induced autophagy and cell death
in TPC1 cells, and the cell death effect of TRAIL was ameliorated by ATG7 siRNA, indicating anti-survival
effect of TRAIL-induced autophagy, while in FRO cells, only cell death, not autophagy, was induced by
TRAIL, but, similar to TPC1, TRAIL-induced cell death was impaired by ATG7 siRNA, indicating anti-
survival effect of basal level of autophagy (NOTE - only LC3-II levels were determined in TRAIL-treated
TPC1 cells.) . In another study, family with sequence similarity 129 member A (FAM129A) induced
[98]
autophagy in parental PCCL3 cells, but inhibited RET/PTC-induced autophagy in RET/PTC-transfected
PCCL3 and thyroid cancer cell lines PTC1 and FTC-236 (NOTE - mCherry-eGFP-LC3B produced yellow
[99]
color in FAM129A-transfected PCCL3 cells, indicating FAM129A-inhibition, not induction, of autophagy.) .

(4) Possible reasons for inconsistent data
Although the reason(s) for these discrepant data are at present unclear, possible explanations are discussed
below.

Obviously, autophagy is originally recognized as a pro-survival stress response, so that it is not difficult
to acknowledge the pro-survival effect of autophagy on cancer cells. Indeed autophagy in general inhibits
[19]
apoptosis (and vice versa), albeit with some exceptions (see below), thereby autophagy inhibition