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Table 1. Tumor-promoting properties of GSK3b reported in bone and soft tissue sarcomas
Tumor type Tumor-promoting properties and underlying mechanisms Ref. No.*
Osteosarcoma GSK3b promotes tumor cell survival, proliferation, and low responsiveness to chemotherapy via the [41,45]
NF-κB-mediated pathway.
Deregulated GSK3b sustains tumor cell survival and proliferation via suppression of the Wnt/ [46]
b-catenin osteosarcoma suppressor pathway.
The therapeutic effect of degalactotigonin (a natural compound from Solanum nigrum L.) against [50]
osteosarcoma depends on GSK3b inactivation-mediated repression of the Hh/Gli1 pathway.
Rhabdomyosarcoma
Alveolar-type GSK3b phosphorylates and sustains the transcriptional activity of PAX3-FOXO1 fusion proto- [62]
oncoprotein in tumor cells.
Embryonal-type GSK3b sustains proliferation and inhibits differentiation of self-renewing, tumor-propagating cells [64]
via suppression of the canonical Wnt/b-catenin pathway.
Synovial sarcoma and Aberrant expression and activity of GSK3b sustains survival, proliferation, and invasion of [79]
fibrosarcoma tumor cells through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix
degradation machinery.
*Respective reference numbers correspond to the references cited in the text. GSK3b: glycogen synthase kinase 3b; NF-κB: nuclear
factor kappa-light-chain-enhancer of activated B cells; Hh: hedgehog; PAX3: paired box 3; FOXO1: forkhead box O-subfamily 1; CDK:
cyclin-dependent kinase

type tyrosine kinases (e.g., VEGFR, PDGFR, and c-Kit), cyclin-dependent kinases (CDKs; e.g., CDK4
and CDK6), pro-oncogenic signaling pathways (e.g., Hh and mTOR), the bone microenvironment (e.g.,
osteoclasts), and immune checkpoint systems. Most trials are in early phases (I and/or II) and none of the
targeted agents have so far been approved for the treatment of osteosarcoma [13,16,36,39,40] .

During the past decade, GSK3b has been proposed as a potential therapeutic target in bone and soft tissue
sarcomas including osteosarcoma [Table 1]. An earlier study showed an inverse association between the
[41]
level of pGSK3b (inactive form) and the capacity of tumor formation in human osteosarcoma cells .
S9
This study also demonstrated the role of a constitutively active form of GSK3b (artificial transversion of
S9 to alanine) in promoting tumor proliferation. Moreover, it was shown that lithium chloride, an ATP-
[42]
non-competitive and non-specific GSK3b inhibitor , attenuated the proliferation of osteosarcoma cells,
induced their apoptosis and enhanced the efficacy of doxorubicin and methotrexate against sarcoma cells.
The therapeutic effect of lithium against tumor cells was shown to be associated with reduced activation of
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) , consistent with studies showing
[41]
that GSK3b is indispensable for the NF-κB-mediated pro-survival pathway [43,44] . Subsequently, another
study showed overexpression of GSK3b in primary osteosarcomas, and induction of apoptosis in sarcoma
[45]
cells following treatment with a pharmacological GSK3b inhibitor that reduced Bcl-2 expression . Our
work has shown that the expression of GSK3b and level of pGSK3b (active form) in osteosarcoma cells
Y216
S9
was higher than in normal osteoblasts, but the level of pGSK3b was lower. We also demonstrated that
GSK3b-specific inhibitors and RNA interference attenuated the survival and proliferation of tumor cells
and induced apoptosis, while sparing normal osteoblasts. The effect of GSK3b inhibition against tumor
cells was coincident with reduced phosphorylation of GSK3b-phospho-acceptor sites in b-catenin and
[46]
with increased b-catenin expression, nuclear translocalization, and co-transcriptional activity . Our
results suggest the therapeutic effects of GSK3b inhibition are associated with the activation of b-catenin,
a putative tumor suppressor in osteosarcoma [47,48] . However, the role of the Wnt/b-catenin pathway in
[49]
the development of osteosarcoma remains controversial . A recent study reported that the therapeutic
effect of degalactotigonin (a natural compound from Solanum nigrum L.) against osteosarcoma occurred
via GSK3b inactivation-mediated repression of the Hh/Gli1 pathway, thus indirectly suggesting a pro-
[50]
tumorigenic role for GSK3b . As discussed in FUTURE PERSPECTIVES FOR GSK3b IN SARCOMA
BIOLOGY AND THERAPY, the GSK3b/b-catenin axis has opposing roles in normal osteogenesis and in
the osteoclastic process. A series of studies described here have helped to understand the biology of GSK3b
and identified it as a promising target for the treatment of osteosarcoma [Figure 1]. These advances should
[51]
facilitate the development of new GSK3b inhibitors for this refractory disease .