ABSTRACT
Anaplastic thyroid cancer (ATC) is one of the most lethal types of human tumors. Lenvatinib can improve the disease control and prognosis in patients with ATC. However, there is an unmet need to develop a therapeutically safer and non-invasive strategy that improves the efficacy of lenvatinib for advanced ATC tumors, which grow larger close to the skin. We previously demonstrated that the topical application of an ointment incorporating tumor suppressive microRNA (TS-miR), miR-634, is a useful strategy as a TS-miR therapeutics. Here, we found that the overexpression of miR-634 synergistically increased lenvatinib-induced cytotoxicity by concurrently downregulating multiple genes related to cytoprotective processes, including ASCT2, a glutamine transporter, in ATC cell lines. Furthermore, the topical application of a miR-634 ointment on subcutaneous tumors effectively augmented the anti-tumor effects of lenvatinib in an ATC xenograft mouse model. Thus, we propose topical treatment of a miR-634 ointment as a rational strategy for improving lenvatinib-based therapy for ATC.
ABSTRACT
The metabolism in tumors is reprogrammed to meet its energetic and substrate demands. However, this metabolic reprogramming creates metabolic vulnerabilities, providing new opportunities for cancer therapy. Metabolic vulnerability as a therapeutic target in esophageal squamous cell carcinoma (ESCC) has not been adequately clarified. Here, we identified pyruvate dehydrogenase (PDH) component X (PDHX) as a metabolically essential gene for the cell growth of ESCC. PDHX expression was required for the maintenance of PDH activity and the production of ATP, and its knockdown inhibited the proliferation of cancer stem cells (CSCs) and in vivo tumor growth. PDHX was concurrently upregulated with the CD44 gene, a marker of CSCs, by co-amplification at 11p13 in ESCC tumors and these genes coordinately functioned in cancer stemness. Furthermore, CPI-613, a PDH inhibitor, inhibited the proliferation of CSCs in vitro and the growth of ESCC xenograft tumors in vivo. Thus, our study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex-associated metabolic vulnerability.
Subject(s)
Cell Proliferation/genetics , Esophageal Neoplasms/genetics , Esophageal Squamous Cell Carcinoma/genetics , Neoplasm Proteins/genetics , Pyruvate Dehydrogenase Complex/genetics , Animals , Caprylates/pharmacology , Cell Proliferation/drug effects , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/therapy , Heterografts , Humans , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Proteins/metabolism , Neoplasm Transplantation , Pyruvate Dehydrogenase Complex/antagonists & inhibitors , Pyruvate Dehydrogenase Complex/metabolism , Sulfides/pharmacology , Up-RegulationABSTRACT
Tinnitus is a common symptom caused by numerous diseases. The etiology is unknown in most cases; however, nasopharyngeal lesions may cause a certain tinnitus. We herein report a case of nasopharyngeal inverted papilloma which presents with rustling tinnitus as the sole initial symptom. The tympanic membrane was intact, and results of hearing test and impedance audiometry were normal. However, sonotubometry showed a complete blockage of the Eustachian tube. A large tumor was found that originated from the choana and occupied the nasopharynx which caused a rustling sound when she swallowed or spoke. Tinnitus totally subsided after removal of this tumor. To our knowledge, the tumor origin and presenting symptom of this case are very rare, and nasopharyngeal examination is required in the diagnosis of unknown hearing symptoms.
