RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation

Abstract

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.

Cyclin‐dependent kinase 5 promotes the growth of tongue squamous cell carcinoma through the microRNA 513c‐5p/cell division cycle 25B pathway and is associated with a poor prognosis

“…Zhou et al 29 observed that, in nonsmall cell lung cancer, CDK5 activates the FAK/AKT signaling pathway to promote tumor angiogenesis. In medullary thyroid carcinoma, the retinoblastoma protein controls the transition of cells from G0/G1 phase to S phase by isolating transcription factor E2F, thereby altering the cell cycle 30 . In prostate cancer, CDK5 interacts with Ser‐727 in transcription activator 3 and phosphorylates the transcription factor androgen receptor, which is a prerequisite for cell proliferation 31,32 .…”

“…In medullary thyroid carcinoma, the retinoblastoma protein controls the transition of cells from G0/G1 phase to S phase by isolating transcription factor E2F, thereby altering the cell cycle. 30 In prostate cancer, CDK5 interacts with Ser-727 in transcription activator 3 and phosphorylates the Cancer May 1, 2022 transcription factor androgen receptor, which is a prerequisite for cell proliferation. 31,32 Some literature suggests that an investigation of specific processes performed by CDK5 phosphorylation dual-specific phosphatase CDC25 family members (including CDC25A-CDC25C) is crucial for identifying factors that lead to the occurrence and development of TSCC, and we plan to investigate those processes in future studies.…”

Antrodia salmonea Extracts Regulate p53-AR Signaling and Apoptosis in Human Prostate Cancer LNCaP Cells

“…Experiments were performed as previously described [ 23 ]. Briefly, after treatment, the collected cells were lysed in lysis buffer for 45 minutes on ice, followed by 15,400 g and 20 minutes of centrifugation to obtain protein extract.…”

Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways

“…The RET (rearranged during transfection) transmembrane receptor protein–tyrosine kinase is highly expressed in medullary thyroid cancer. In their study, Yue et al [ 6 ] demonstrate that GDNF (Glial Cell Line-Derived Neurotrophic Factor) stimulated RET phosphorylation and resulted in a physical interaction with CDK5 and its activation by phosphorylation. Activated CDK5 further caused STAT3 activation through Ser727 phosphorylation Moreover, they also found that GDNF treatment enhanced ERK1/2 and EGR1 transcriptional regulator activity, which is involved in p35 activation.…”