Up Regulation of Somatostatin Receptor Expression on Medullary Thyroid Cancers Using HDACi

Introduction: Medullary Thyroid Cancers (MTC) are neuroendocrine tumors (NETs) arising from C-cells of the thyroid gland. MTCs are frequently metastatic and also secrete excessive hormones. Somatostatin receptors (SSTRs) are... [ view full abstract ]

Introduction: Medullary Thyroid Cancers (MTC) are neuroendocrine tumors (NETs) arising from C-cells of the thyroid gland. MTCs are frequently metastatic and also secrete excessive hormones. Somatostatin receptors (SSTRs) are overexpressed in NETs. Somatostatin (SST) analogs have been used to treat and image NETs, but have not shown to be very practical in MTCs due to low SSTR expression. Herein, we describe the novel use of a class of drugs known as histone deacetylase inhibitors (HDACi) that have the unique ability to up regulate expression of SSTRs on MTCs. The use of HDACi will further advance SST analog therapies imaging studies in NETs.

Methods: Quantitative PCR (Q-PCR) was used to evaluate basal expression of SSTRs on two MTC cell lines. Time and dose dependent induction for SSTRs were assessed using four separate HDACi-- FK228, SAHA, TDP-A and VPA-- using Q-PCR and Western Blot analysis.

Results: Basal expression for both cell lines showed an increased expression in one or more SSTRs. After Treatment with HDACi, both MZ and TT cells showed a dramatic increase in SSTRs at message and protein levels. More importantly, TT cells had no basal expression of SSTR4, but treatment showed to actually induce expression of SSTR4.

Conclusion: We demonstrated that HDACi increased message and protein levels of SSTRs in MTC cells in a time and dose dependent manner. We also showed that HDACi have the capability to induce expression of SSTRs with no basal expression. This novel finding provides an avenue to improve SST analog therapies for MTCs.