The Development of novel therapeutic strategy for anaplastic thyroid carcinoma by manipulating the ubiquitin-proteasome activity

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Anaplastic thyroid carcinoma is a poorly differentiated carcinoma found in elderly people. The patients with anaplastic carcinoma always suffer from poor prognosis. It is an urgent business to develop the effective strategy to suppress the growth of anaplastic carcinoma and prolong the prognosis of patients. We focused on the ubiqitin-proteasome system. Proteasome is a major intracellular proteinase found as a large protein complex composed of at least 14 distinct but homologous subunits with molecular masses of 21-32 kD and they are assembled into an approximately 700 kDa cylindcal structure. It is involved in the destruction of regulatory proteins responsible for biological processes such as cell cycle progression. We analyzed the expression of proteasome subunits in anaplastic thyroid carcinoma and found that proteasome subunit C2 and proteasome activator g (PA28g) are highly expressed in its rapid-growing cancer cells. This result is repeatedly confirmed by western blotting and imm … More unocytochemistry, when other types of thyroid carcinoma were also estimated. Interestingly, PA 28g is localized in nuclei of cancer cells, suggesting PA28g could be one of the good candidate for manipulating the growth of cancer cells. We then analyzed the detailed turn-over of PA28g using rat functional thyroid cell line, FRTL5 cells. The growth-stimuli, TSH and insulin, induced PA28-γ expression in FRTL5 cell. Intere stingly, both treatment not only upregulate PA28-γ expression but also recruite PA28-γ from cytosol to nucleus. The combination of TSH and insulin showed highest inducibility of PA28-γ as well as dual DNA synthesis of FRTL5. Proteasome inhibitors such as lactacystin significantly blocked the DNA synthesis induced by TSH and insulin, indicating the intrinsic 20S proteasome is involved in thyroid cell growth. Thus, our results indicate PA28-γ is induced by goitrogenic factors, TSH and insulin, in thyroid cell and potentially contribute to thyroid cell growth by potentiating 20S proteasome activity.Taken together, overexpressed proteasome component such as C2 or PA28-γ will be good candidates for manipulating proteasome activity, thereby interfering with anaplastic cancer cell growth. Less