Vismodegib Potentiates Marine Antimicrobial Peptide Tilapia Piscidin 4-Induced Cytotoxicity in Human Non-Small Cell Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) is a common cancer with several accepted treatments, such as chemotherapy, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and immune checkpoint inhibitors. Nevertheless, NSCLC cells often become insensitive to these treatments, and therapeutic resistance is a major reason NSCLC still has a high mortality rate. The induction of therapeutic resistance in NSCLC often involves hedgehog, and suppression of hedgehog can increase NSCLC cell sensitivity to several conventional therapies. In our previous work, we demonstrated that the marine antimicrobial peptide tilapia piscidin 4 (TP4) exhibits potent anti-NSCLC activity in both EGFR-WT and EGFR-mutant NSCLC cells. Here, we sought to further explore whether hedgehog might influence the sensitivity of NSCLC cells to TP4. Our results showed that hedgehog was activated by TP4 in both WT and EGFR-mutant NSCLC cells and that pharmacological inhibition of hedgehog by vismodegib, a Food and Drug Administration-approved hedgehog inhibitor, potentiated TP4-induced cytotoxicity. Mechanistically, vismodegib acted by enhancing TP4-mediated increases in mitochondrial membrane potential and intracellular reactive oxygen species (ROS). MitoTempo, a specific mitochondrial ROS scavenger, abolished vismodegib/TP4 cytotoxicity. The combination of vismodegib with TP4 also reduced the levels of the antioxidant proteins catalase and superoxide dismutase, and it diminished the levels of chemoresistance-related proteins, Bcl-2 and p21. Thus, we conclude that hedgehog regulates the cytotoxic sensitivity of NSCLC cells to TP4 by protecting against mitochondrial dysfunction and suppressing oxidative stress. These findings suggest that combined treatment of vismodegib and TP4 may be a promising therapeutic strategy for NSCLC.

Overexpression of a Novel ERF-X-Type Transcription Factor, OsERF106MZ, Reduces Shoot Growth and Tolerance to Salinity Stress in Rice.

Transcription factors (TFs) such as ethylene-responsive factors (ERFs) are important for regulating plant growth, development, and responses to abiotic stress. Notably, more than half of the rice ERF-X group members, including ethylene-responsive factor 106 (OsERF106), are abiotic stress-responsive genes. However, their regulatory roles in abiotic stress responses remain poorly understood. OsERF106, a salinity-induced gene of unknown function, is annotated differently in RAP-DB and MSU RGAP. In this study, we isolated a novel (i.e., previously unannotated) OsERF106 gene, designated OsERF106MZ (GenBank accession No. MZ561461), and investigated its role in regulating growth and the response to salinity stress in rice. OsERF106MZ is expressed in germinating seeds, primary roots, and developing flowers. Overexpression of OsERF106MZ led to retardation of growth, relatively high levels of both malondialdehyde (MDA) and reactive oxygen species (ROS), reduced catalase (CAT) activity, and overaccumulation of both sodium (Na+) and potassium (K+) ions in transgenic rice shoots. Additionally, the expression of OsHKT1.3 was downregulated in the shoots of transgenic seedlings grown under both normal and NaCl-treated conditions, while the expression of OsAKT1 was upregulated in the same tissues grown under NaCl-treated conditions. Further microarray and qPCR analyses indicated that the expression of several abiotic stress-responsive genes such as OsABI5 and OsSRO1c was also altered in the shoots of transgenic rice grown under either normal or NaCl-treated conditions. The novel transcription factor OsERF106MZ negatively regulates shoot growth and salinity tolerance in rice through the disruption of ion homeostasis and modulation of stress-responsive gene expression.