ABSTRACT
Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5-3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38ß, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.
Subject(s)
Cell Proliferation/drug effects , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mitogen-Activated Protein Kinase 14/genetics , Combined Modality Therapy , Dasatinib/pharmacology , Drug Resistance, Neoplasm/genetics , Fusion Proteins, bcr-abl/antagonists & inhibitors , Gene Knockdown Techniques , Genetic Therapy , Humans , Imatinib Mesylate/pharmacology , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Mitogen-Activated Protein Kinase 14/deficiency , Protein Kinase Inhibitors/pharmacologyABSTRACT
Perturbed Nicotinamide adenine dinucleotide (NAD+) homeostasis is involved in cancer progression and metastasis. Quinolinate phosphoribosyltransferase (QPRT) is the rate-limiting enzyme in the kynurenine pathway participating in NAD+ generation. In this study, we demonstrated that QPRT expression was upregulated in invasive breast cancer and spontaneous mammary tumors from MMTV-PyVT transgenic mice. Knockdown of QPRT expression inhibited breast cancer cell migration and invasion. Consistently, ectopic expression of QPRT promoted cell migration and invasion in breast cancer cells. Treatment with QPRT inhibitor (phthalic acid) or P2Y11 antagonist (NF340) could reverse the QPRT-induced invasiveness and phosphorylation of myosin light chain. Similar reversibility could be observed following treatment with Rho inhibitor (Y16), ROCK inhibitor (Y27632), PLC inhibitor (U73122), or MLCK inhibitor (ML7). Altogether, these results indicate that QPRT enhanced breast cancer invasiveness probably through purinergic signaling and might be a potential prognostic indicator and therapeutic target in breast cancer.
Subject(s)
Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Cell Movement/physiology , Myosin Light Chains/metabolism , Pentosyltransferases/biosynthesis , Animals , Breast Neoplasms/genetics , Female , Humans , MCF-7 Cells , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myosin Light Chains/genetics , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Pentosyltransferases/deficiency , Pentosyltransferases/genetics , Phosphorylation/physiologyABSTRACT
Increased aerobic glycolysis portends an unfavorable prognosis in thyroid cancer. The metabolic reprogramming likely results from altered mitochondrial activity and may promote cancer progression. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) plays a pivotal role in mitochondrial biogenesis and function. In the present study, we aimed to evaluate the clinicopathological significance of PGC1α expression and the potential effects of PGC1α modulation. Firstly, the expression of PGC1α in thyroid cancer samples was evaluated using western blot analysis and immunohistochemical staining. Compared with normal thyroid tissue, PGC1α expression was downregulated in thyroid cancer. PGC1α-negative papillary cancer was associated with BRAF V600E mutation, large tumor size, extrathyroidal or lymphovascular invasion, lymph node metastasis, and advanced stage. The results were consistent with the analysis of The Cancer Genome Atlas data. PGC1α expression correlated with oxygen consumption in thyroid cancer cells and was inversely related to AKT activity. The biologic relevance of PGC1α was further investigated by gain- and loss-of-function experimental studies. PGC1α overexpression led to augmented oxidative metabolism and accelerated tumor growth, whereas PGC1α knockdown induced a glycolytic phenotype but reduced tumor growth in vivo. In conclusion, PGC1α downregulation is associated with glycolytic metabolism and advanced disease in thyroid cancer. Nonetheless, manipulating PGC1α expression and metabolic phenotype does not necessarily translate into beneficial effects. It suggests that the metabolic phenotype is likely the consequence rather than the cause of disease progression in thyroid cancer.
