Pharmacological suppression of the Ras/MAPK pathway in thyroid carcinoma cells can provoke opposite effects on cell migration and proliferation: The appearance of yin-yang effects and the need of combinatorial treatments

Abstract

A major challenge in tumor therapy is the decrease or even the halting of cell proliferation and migration of cancerous cells. In the present study, we have analyzed the impact of a pharmacological blockade of the PI3K/Akt and MAPK/ERK1/2 signaling pathways on cell migration, proliferation and cell death in three human thyroid tumor cell lines that represent the main types of malignant thyroid carcinomas (B-CPAP, follicular; Cal-62, anaplastic; FTC-133, papillary thyroid carcinoma cells) and in which these pathways are constitutively activated. In general, pharmacological perturbation of PI3/Akt (application of MK-2206) and MEK/ERK1/2 (application of PD0325901 or U0126) signaling led to a cell line and drug-specific decrease in the proliferation and migration potential of thyroid carcinoma cells, although to a varying extent. However, one exception became apparent: in Cal-62 cells inhibition of the MEK/ERK1/2 module increased the migration rate up to 50%. This effect could be prevented by a simultaneous suppression of the PI3/Akt pathway, but also by application of the multiple kinase inhibitor sorafenib, a treatment that did not change the activation state of Akt. Thus, a pharmacological perturbation of canonical signaling pathways in thyroid carcinoma may induce drug-dependent yin-yang effects that are characterized by a simultaneous suppression of one (i.e., proliferation) and the activation of another (i.e., migration) cellular process. The appearance of such phenomena should be taken into account when therapy plans are established.

The circEPSTI1/mir-942-5p/LTBP2 axis regulates the progression of OSCC in the background of OSF via EMT and the PI3K/Akt/mTOR pathway

“…c Characteristic IHC staining of p-PI3K, p-Akt, and p-mTOR in circEPSTI1 high /miR-942-5p low and circEPSTI1 low /miR-942-5p high OSCC tissues. ***P < 0.001; **P < 0.01; *P < 0.05. cell proliferation, invasion, and apoptosis and, when deregulated, promotes tumorigenesis 36 .…”

“…For the first time, we identified the PI3K/Akt signaling pathway as the most altered pathway between the circEPSTI1 high /miR-942-5p low and circEPSTI1 low /miR-942-5p high profiles. The PI3K/Akt signaling pathway regulates cell proliferation, invasion, and apoptosis and, when deregulated, promotes tumorigenesis 36 .…”

A Novel Orally Active Inverse Agonist of Estrogen-related Receptor Gamma (ERRγ), DN200434, A Booster of NIS in Anaplastic Thyroid Cancer

“…To evaluate the biological potential of DN200434, we determined its effects on radioiodine uptake in CAL62 cells carrying KRAS gene mutations, which have been utilized to examine the therapeutic efficacy of several agents, allowing cellular cytotoxicity induction and iodide-handling gene restoration (20)(21)(22). DN200434 induced a dose-and time-dependent increase in radioiodine incorporation in CAL62 cells, which was inhibited to basal levels by KClO 4 as an NIS-specific inhibitor (1, 23), suggesting that the increased radioiodine uptake was linked to DN200434-modulated NIS function.…”

Activation of CXCL5-CXCR2 axis promotes proliferation and accelerates G1 to S phase transition of papillary thyroid carcinoma cells and activates JNK and p38 pathways

“…The role of p38 and JNK MAPK pathways in cancer cells is controversial 24,25 . Both activation and deactivation of p38 and JNK pathways have been reported to contribute to aggressive tumor behaviors of thyroid cancer cells [26][27][28] .…”