Abstract
The constitutive activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signal transduction is well elucidated in STAT3-mediated oncogenesis related to thyroid cancer and is considered to be a plausible therapeutic target. Hence, we investigated whether curcumin, a natural compound, can target the JAK/STAT3 signaling pathway to induce cytotoxic effects in papillary thyroid cancer (PTC) cell lines (BCPAP and TPC-1) and derived thyroid cancer stem-like cells (thyrospheres). Curcumin suppressed PTC cell survival in a dose-dependent manner via the induction of caspase-mediated apoptosis and caused the attenuation of constitutively active STAT3 (the dephosphorylation of Tyr705–STAT3) without affecting STAT3. Gene silencing with STAT3-specific siRNA showed the modulation of genes associated with cell growth and proliferation. The cotreatment of PTC cell lines with curcumin and cisplatin synergistically potentiated cytotoxic effects via the suppression of JAK/STAT3 activity along with the inhibition of antiapoptotic genes and the induction of proapoptotic genes, and it also suppressed the migration of PTC cells by downregulating matrix metalloproteinases and the inhibition of colony formation. Finally, thyrospheres treated with curcumin and cisplatin showed suppressed STAT3 phosphorylation, a reduced formation of thyrospheres, and the downregulated expression of stemness markers, in addition to apoptosis. The current study’s findings suggest that curcumin synergistically enhances the anticancer activity of cisplatin in PTC cells as well as in cancer stem-like cells by targeting STAT3, which suggests that curcumin combined with chemotherapeutic agents may provide better therapeutic outcomes.
Highlights
Malignancies of the human thyroid gland or thyroid carcinoma (TC) represent the most prevalent cancers of the endocrine system and has been ranked as the seventh common cancer type with relatively higher incidence rate [1]
We wanted to know whether curcumin-mediated cell cycle arrest would lead to apoptosis, so in a series of experiments, we first checked the effect of curcumin on the cell cycle, and our data demonstrated a remarkable increase in the SubG0/G1 phase of BCPAP cell lines treated with curcumin for 24 h (Supplementary Materials, Figure S1A)
papillary thyroid cancer (PTC) cells were treated with 10 μM, 20 μM, and 40 μM of curcumin for 24 h, and an expression analysis of various apoptotic markers was done, which clearly showed that curcumin treatment caused apoptosis via the activation of caspases through the mitochondrial apoptotic pathway, as treatment with curcumin led to a significant decrease in the mitochondrial membrane potential (MMP) of BCPAP, as shown in the Supplementary Materials, Figure S1C,D
Summary
Malignancies of the human thyroid gland or thyroid carcinoma (TC) represent the most prevalent cancers of the endocrine system and has been ranked as the seventh common cancer type with relatively higher incidence rate [1]. The treatment options available for thyroid malignancies are effective if diagnosed at an early stage (mainly surgery and radioiodine remnant ablation), there are more challenges in treating metastasized and relapsed forms of thyroid cancer, requiring a deep and thorough reinvestigation aimed at better therapeutic outcomes. Deregulated functioning of cell survival signaling pathways is the main driver for the various hallmarks of carcinogenesis, including incessant cell proliferation and drug resistance. A number of oncogenic signaling molecules and pathways have been deregulated in all three types of thyroid cancer development. Various investigations have shown that PI3K and MAPK are the most centric cascades of thyroid carcinogenesis, reflecting a web of complex and interconnected molecules and pathways
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