rottlerin and Carcinoma--Non-Small-Cell-Lung

Rottlerin, a polyphenolic compound derived from Mallotus philipinensis, has been reported to exhibit anti-tumor activities in a variety of human malignancies including NSCLC (non-small cell lung cancer). TAZ (transcriptional co-activator with PDZ-binding motif), one of the key activators in Hippo pathway, has been characterized as an oncoprotein. Therefore, inhibition of TAZ could be useful for the treatment of human cancers. In the current study, we aimed to explore whether rottlerin inhibits the expression of TAZ in NSCLC, leading to its anti-cancer activity. Multiple approaches were applied for determining the mechanism of rottlerin-mediated anti-tumor function, including cell growth assay, Flow cytometry, wound healing assay, invasion assay, Western blotting, and transfection. We found that rottlerin inhibited cell growth, triggered apoptosis, arrested cell cycle, and retarded cell invasion in NSCLC cells. Moreover, our results showed that overexpression of TAZ enhanced cell growth, stimulated apoptosis, and promoted cell migration and invasion. Consistently, inhibition of TAZ exhibited anti-tumor activity in NSCLC cells. Notably, we validated that rottlerin exerted its tumor suppressive function via inactivation of TAZ in NSCLC cells. Taken together, our study indicates that inhibition of TAZ by rottlerin could be a promising strategy for the prevention and therapy of NSCLC.

Topics: A549 Cells; Acetophenones; Antineoplastic Agents, Phytogenic; Benzopyrans; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Neoplasm Invasiveness; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Transfection

Drugs that target protein kinase C (PKC) are now being evaluated in patients with non-small cell lung cancer (NSCLC), but the role of PKC in NSCLC cells remains unclear. We report here that NSCLC cell lines show enhanced phosphorylation and altered expression of specific PKC isoforms compared with normal lung epithelial cells. PKC inhibition variably increased apoptosis, with rottlerin, a PKCdelta inhibitor, being most effective and potentiating chemotherapy-induced apoptosis, especially with trastuzumab. Consistent with PKCdelta being anti-apoptotic in NSCLC cells, transient transfection of a kinase-dead mutant of PKCdelta increased apoptosis and potentiated chemotherapy-induced apoptosis. Our studies provide a rationale for targeting PKC isoforms in NSCLC cells, especially PKCdelta.

Topics: Acetophenones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzopyrans; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Inhibitors; Humans; Isoenzymes; Lung Neoplasms; Phosphorylation; Protein Kinase C; Protein Kinase C-delta; Transfection; Trastuzumab