Abstract
Tanshinone IIA (TIIA) is a diterpenoid naphthoquinone isolated from the herb Salvia miltiorrhiza with antitumor effects manifested at multiple levels that are mechanistically obscure. In our previous studies, we illustrated that TIIA treatment triggered apoptosis in human osteosarcoma 143B cells both in vitro and in vivo, accompanied with mitochondrial dysfunction. Importantly, the overall survival rate of patients with osteosarcoma who were randomly recruited to S. miltiorrhiza treatment was significantly higher than those without. Pursuing this observation, we evaluated the potential effect of TIIA on autophagy induction in osteosarcoma both in vivo and in vitro. We discovered that TIIA inhibited osteosarcoma cell survival through class I PI3K and Akt signaling pathways. In contrast, expression of class III PI3K required in the early stages of autophagosome generation was predominantly enhanced by TIIA treatment. Our study indicated that treatment of TIIA effectively induced autophagy in human osteosarcoma cells, which contributed to the blockade of anchorage-independent growth of osteosarcoma cells and ameliorated tumor progression in NOD/SCID mice. We demonstrated that TIIA-mediated autophagy occurred in a sestrin 2 (SESN2)-dependent but not Beclin 1-dependent manner. In addition, we defined the activation of HGK (MAP4K4 or mitogen-activated protein kinase kinase kinase kinase)/SAPK/JNK1/Jun kinase pathways in upregulating transcription of SESN2, in which TIIA triggered HGK/JNK1-dependent Jun activation and led to increased Jun recruitment to AP-1-binding site in the SESN2 promoter region. Our results offer novel mechanistic insight into how TIIA inhibits osteosarcoma growth and suggest TIIA as a promising therapeutic agent for the treatment of cancer.
Highlights
Osteosarcoma, a highly aggressive tumor arising in long bones, is the most commonly occurring primary malignancy in teenagers and young adults, with a broad spectrum of morphologies
We found that Tanshinone IIA (TIIA) effectively inhibited the growth of osteosarcoma cells both in vitro and in vivo and a provocative observation from this study led us to novel discoveries that extended beyond the popular proliferative and oncogenic roles of certain kinases and inhibition of these kinases by specific agents for tumor growth inhibition
Hematopoietic progenitor kinase-germinal cell kinaselike kinase (HGK) is known to be correlated with worse prognosis of several cancers[31,32,33] and interact with Pyk[2], which contributes to glioma cell migration[34]
Summary
Osteosarcoma, a highly aggressive tumor arising in long bones, is the most commonly occurring primary malignancy in teenagers and young adults, with a broad spectrum of morphologies. In our previous study[15], we found that TIIA administration resulted in a decrease in the mitochondrial fusion proteins, Mfn1/2 and Opa[1], as well as an increase in the fission protein Drp[1], which contributed to caspase cascade-mediated apoptosis in 143B osteosarcoma cells. These studies suggest that TIIA might be a promising agent for the prevention and/or treatment of osteosarcoma; a complete understanding of the underlying molecular mechanism of TIIA-mediated signaling networks in osteosarcoma growth inhibition remains wanting
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