Abstract
Background: Papillary thyroid cancer (PTC) is a general thyroid cancer subtype, however, PTC may develop metastasize or become recurrent via anti-cancer drug resistance, rendering it practically incurable. Therefore, effective and reliable clinical approaches are urgently required.
Methods: In this study, we demonstrated the coordinated upregulation of SERCA1 in metastatic PTC under anti-cancer drug treated conditions. SERCA1, in turn, is transcriptionally upregulated by CaMK2α via nuclear translocated NFκB. we propose a clinical approach that screens novel drug candidates based on target identification and numerous survival-involved gene validation in a patient-derived anti-cancer drug-resistant mediated lymph node metastatic PTC model. Results of lymph node metastatic PTC was compared to anti-cancer drug sensitive and main mass PTC on in vitro and in vivo model.
Results: Consequently, we identified sarco/endoplasmic reticulum (ER) calcium ATPase 1 (SERCA1) in patient-derived metastatic PTC cells. SERCA1 was considerably increase under anti-cancer drug treated conditions such as sorafenib or lenvatinib by CaMK2α mediated nuclear translocated NFκB. SERCA is a critical component in cytosolic free calcium regulation. However, a cardiac dysfunction was inevitable in vivo because of non-specific inhibition of SERCA isoforms by conventional SERCA inhibitors. This study aimed to design a therapeutic approach with decrease of cardiac dysfunction via SERCA1-isoform specific inhibition by novel small molecules, CKP1 and CKP2 under severe ER stress condition in patient-derived metastatic papillary thyroid cancer. These novel SERCA1-specific inhibitors were remarkably increased tumor shrinkage in the patient-derived metastatic PTC xenograft tumor model without cardiac dysfunctionwhen combination treatment with anti-cancer drug, such as sorafenib and lenvatinib. Conclusively, these findings are clinically significant for novel combinatorial strategy development for effective refractory cancer cell treatments, especially in the case of anti-cancer drug-resistant mediated recurrent and metastatic cancer.
Conclusions
Here, we showed that increase of SERCA1 by CaMK2α mediated nuclear translocated NFκB was fundamentally responsible for cellular resistant for cytotoxic stress under sorafenib or levatinib treatment. These outcomes suggest progress for the novel combinatorial scheme that uses targeted therapy to treat malignant cancer cells, such as anti-cancer drug-resistant cancer cells.