Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Upregulation of SMAD4 inhibits thyroid cancer cell growth via MAPK/JNK pathway repression

Huiyao Cai , Xinna Yang, Zhengrong Jiang, Bo Liang, Qingyan Cai, Huibin Huang

Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, 362000, Fujian, China;

For correspondence:- Huiyao Cai Email: HuiyaoCaidft@163.com Tel:+86595362000

Accepted: 27 November 2019 Published: 30 December 2019

Citation: Cai H, Yang X, Jiang Z, Liang B, Cai Q, Huang H. Upregulation of SMAD4 inhibits thyroid cancer cell growth via MAPK/JNK pathway repression. Trop J Pharm Res 2019; 18(12):2473-2478 doi: 10.4314/tjpr.v18i12.2

© 2019 The authors.
This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited..

Abstract

Purpose: To investigate whether the effect of mothers against decapentaplegic homolog 4 (SMAD4) on thyroid cancer cell survival was via the MAPK/JNK pathway.

Methods: Papillary thyroid cancer (TPC)-1 cells were cultured and transfected with SMAD4 overexpression plasmid or siRNA to achieve SMAD4 overexpression or knockdown, respectively. In TPC-1 cells, the mRNA and protein expression levels of SMAD4, mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) were quantified using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Cell viability and apoptosis were measured using MTT assay and flow cytometry, respectively. MAPK and JNK inhibitors (U0126 and SP600125) were used for rescue experiments. The sensitivity of TPC-1 cells to chemotherapeutic drugs, cisplatin and doxorubicin, was also assessed.

Results: A reduction in viability and an enhancement in apoptosis (p < 0.01) were found when SMAD4 was overexpressed in TPC-1 cells. Knockdown of SMAD4 elicited opposite results (p < 0.01). Overexpression of SMAD4 caused a decrease in the activation of MAPK and JNK, as evidenced by lower levels of phosphorylated MAPK and phosphorylated JNK (p < 0.05). Results from rescue experiments indicate that the increase in cell viability after SMAD4 knockdown was reversed by MAPK/JNK inhibitors (p < 0.05 and p < 0.01). Finally, overexpression of SMAD4 increased cytotoxic susceptibility of thyroid cancer cells to cisplatin/doxorubicin.

Conclusion: These results indicate that SMAD4 inhibits thyroid cancer cell growth via inactivation of MAPK/JNK pathway. Overexpression of SMAD4 also increased thyroid cancer cell sensitivity to cisplatin/doxorubicin.

Keywords: Thyroid cancer, SMAD4, TGF-^6; signaling pathway, MAPK/JNK, Cell survival, Drug sensitivity