Molecular-Targeted Hyperthermia Therapy for Breast Cancer Cells

Abstract

Hyperthermia is a minimally invasive cancer therapy that sensitizes cancer cells to chemotherapy and radiotherapy by improving the tumor microenvironment such as blood flow and acidic conditions. Because stress-related and anti-apoptotic proteins exert a cytoprotective effect and are often up-regulated in many types of cancer, molecular-targeted therapy may be useful in combination with hyperthermia. In the present study, we found that hyperthermia induced myeloid-cell leukemia 1 (MCL-1) anti-apoptotic protein expression among several apoptosis-related molecules. MCL-1 knockdown promoted the anti-tumor effect of hyperthermia by increasing apoptosis. miR-29b-3p, which downregulated MCL-1 protein expression, also promoted the antitumor effect of hyperthermia. Moreover, we showed that hyperthermia facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) stress-related protein to the nucleus and expression of the downstream target heme oxygenase 1 (HO-1) antioxidant gene. The knockdown of Nrf2 promoted the anti-tumor effect of hyperthermia by suppressing expression of stress-related genes such as HO-1 and NAD (P) H quinone dehydrogenase 1 and by increasing reactive oxygen species production. Our results suggest the potential usefulness of molecular-targeted hyperthermia therapy using nucleic acid medicine.