KLF5 influences cell biological function and chemotherapy sensitivity through the JNK signaling pathway in anaplastic thyroid carcinoma

Abstract

We aimed to investigate the effects of Krüppel-like factor 5 (KLF5) on cell biological function and chemotherapy sensitivity of anaplastic thyroid carcinoma (ATC) and explore the underlying mechanism. In this study, we found that KLF5 was expressed higher in ATC cells than that in normal thyroid cells. Knockdown of KLF5 inhibited proliferation, induced apoptosis and restrained invasion and migration abilities of ATC cells. KLF5 overexpression promoted proliferation and inhibited apoptosis of ATC cells in response to doxorubicin (Dox), whereas KLF5 knockdown increased the sensitivity of ATC cells to Dox. Multidrug resistance gene 1/permeability glycoprotein and ATP-binding cassette superfamily G member 2 were heightened in ATC cells with KLF5 overexpression, but the opposite results were found in sh-KLF5-treated cells. Phosphorylation (p)-c-Jun N-terminal kinase (JNK) was upregulated in KLF5 overexpression cells, whereas it was downregulated in the KLF5 knockdown treatment group. Furthermore, KLF5 knockdown inhibited ATC growth and enhanced the Dox sensitivity of ATC by inactivating the JNK signaling pathway. Taken together, our findings concluded that KLF5 knockdown can remarkably inhibit the proliferation, invasion, and migration and induce apoptosis of ATC cells, and increase the chemotherapy sensitivity of ATC, all of which probably through inhibiting the JNK signaling pathway. K E Y W O R D S anaplastic thyroid carcinoma, chemotherapy sensitivity, JNK signaling pathway, KLF5

Kruppel-like factor 13 acts as a tumor suppressor in thyroid carcinoma by downregulating IFIT1

“…High expression of KLF4 in ATC cells is found, and the phenotype and drug resistance in vitro and in vivo shall be maintained [ 24 ]. KLF5 affects biological function and sensitivity to chemotherapy of ATC through the JNK signaling pathway [ 25 ]. KLF9, a target gene of TF4, can induce cell apoptosis in medullary thyroid carcinoma [ 26 ].…”

The roles and regulation of the KLF5 transcription factor in cancers

“…Consistently, KLF5 downregulation promoted cisplatin-induced apoptosis by inhibiting the phosphorylation of the DNA damage checkpoint protein checkpoint kinase 1/2(Chk1/2) in NSCLC 113. KLF5 depletion markedly induced apoptosis of anaplastic thyroid carcinoma cells and increased doxorubicin sensitivity, and likely to be through inhibiting the JNK signaling pathway 114. In contrast, ectopic KLF5 expression was reported to promote apoptosis in ESCC cells115 and in LNCaP prostate cancer cells in the…”

“…113 KLF5 depletion markedly induced apoptosis of anaplastic thyroid carcinoma cells and increased doxorubicin sensitivity, and likely to be through inhibiting the JNK signaling pathway. 114 In contrast, ectopic KLF5 expression was reported to promote apoptosis in ESCC cells 115 and in LNCaP prostate cancer cells in the presence of phorbol 12-myristate 13-acetate (PMA) by activating the JNK signaling pathway. 116 Interestingly, KLF5 inhibited autophagy in castration-resistant prostate cancer cells by suppressing the transcription of BECN1.…”

Zinc finger proteins and ATP‐binding cassette transporter‐dependent multidrug resistance

“…Conversely, in anaplastic thyroid carcinoma, KLF5 overexpression led to increased mRNA levels of ABCB1 and ABCG2 , and KLF5 knockdown enhanced the doxorubicin sensitivity (Table 2). 181 The KLF8 overexpression in gastric carcinoma cell lines was associated with vincristine resistance, potentially linked to ABCB1 overactivity 177 . Therefore, they suggest that TNF‐α/KLF6/ ABCB1b signalling might contribute to TNF‐α‐induced ABCB1b downregulation in an inflammatory context 178 …”