Ameloblastin induces tumor suppressive phenotype and enhances chemosensitivity to doxorubicin via Src-Stat3 inactivation in osteosarcoma

Abstract

Ameloblastin (AMBN), the most abundant non-amelogenin enamel matrix protein, plays a role in ameloblast differentiation. Previously, we found that AMBN promoted osteogenic differentiation via the interaction between CD63 and integrin β1, leading to the inactivation of Src; however, how AMBN affects the malignant behavior of osteosarcoma is still unclear. Osteosarcoma affects the bone and is associated with poor prognosis because of the high rate of pulmonary metastases and drug resistance. Here we demonstrated that stable overexpression of AMBN induced apoptosis and suppressed colony formation and cell migration via the inactivation of Src-Stat3 pathway in human osteosarcoma cells. Moreover, AMBN induced chemosensitivity to doxorubicin. Thus, AMBN induced a tumor suppressive phenotype and chemosensitivity to doxorubicin via the AMBN-Src-Stat3 axis in osteosarcoma. Indeed, immunohistochemical expression of AMBN was significantly correlated with better outcome of osteosarcoma patients. Our findings suggest that AMBN can be a new prognostic marker and therapeutic target for osteosarcoma combined with conventional doxorubicin treatment.

STAT3 and its targeting inhibitors in osteosarcoma

“…Moreover, OS patients with high STAT3 expression had significantly lower survival rate than those without high STAT3 levels 105 . Inhibition of STAT3 may improve the sensitivity of chemotherapy‐resistant OS cell lines to drugs including doxorubicin and cisplatin 77,106,107 . STAT3 deactivation by compounds, such as raddeanin A (RDA), represents a potential therapeutic target to increase chemosensitivity of OS cells 106 .…”

“…OS STAT3 potential therapeutic targets to increase chemosensitivity include AMBN 77 . Src/STAT3 inhibition by AMBN was shown to induce sensitivity to doxorubicin of OS cells 77 . Constitutive activation of STAT3 may lead to chemoresistance of OS, failure of chemotherapy and poor prognosis for OS.…”

Balancing STAT Activity as a Therapeutic Strategy

“…While IL-6 family cytokines are important mediators of STAT3 activation, other cancer-associated receptors can also activate STAT3. STAT3-driven tumor progression can also be achieved by epidermal growth factor receptors (both wild-type EGFR and EGFRvIII), fibroblast growth factor receptors (FGFR), insulin-like growth factor receptor (IGFR), hepatocyte growth factor (HGFR, also known as MET), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), v-src, and Bcr-Abl [119,120,121,122,123,124,125,126,127]. Interestingly, acetylation of STAT3 also induces tumor progression through enhanced pro-tumorigenic IL-17A secretion [128,129].…”

Down‐regulation of PKM2 enhances anticancer efficiency of THP on bladder cancer

“…This indicates that STAT3 plays an important role in the pharmacodynamics of THP. STAT3 is a member of the STAT family of transcription factors and is activated in several cancers including osteosarcoma,8 renal cell carcinoma,9 and pancreatic cancer 10. Inhibition of STAT3 could serve as a potent chemotherapeutic sensitizing strategy to overcome drug resistance in chemoresistant cancer cells 11, 12.…”