dorsomorphin and Lung-Neoplasms

Triptolide, a triterpene extracted from the Chinese herb Tripterygium wilfordii, has been reported to exert multiple bioactivities, including immunosuppressive, anti‑inflammatory and anticancer effects. Although the anticancer effect of triptolide has attracted significant attention, the specific anticancer mechanism in non‑small‑cell lung cancer (NSCLC) remains unclear. The present study aimed to investigate the anticancer effect of triptolide in the H1395 NSCLC cell line and to determine its mechanism of action. The results revealed that triptolide significantly inhibited the cell viability of NSCLC cells in a dose‑dependent manner, which was suggested to be through inducing apoptosis. In addition, triptolide was revealed to activate the calcium (Ca2+)/calmodulin‑dependent protein kinase kinase β (CaMKKβ)/AMP‑activated protein kinase (AMPK) signaling pathway by regulating the intracellular Ca2+ concentration levels, which increased the phosphorylation levels of AMPK and reduced the phosphorylation levels of AKT, ultimately leading to apoptosis. The CaMKKβ blocker STO‑609 and the AMPK blocker Compound C significantly inhibited the apoptosis‑promoting effect of triptolide. In conclusion, the results of the present study suggested that triptolide may induce apoptosis through the CaMKKβ‑AMPK signaling pathway and may be a promising drug for the treatment of NSCLC.

Topics: AMP-Activated Protein Kinases; Apoptosis; Benzimidazoles; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Diterpenes; Epoxy Compounds; Humans; Lung Neoplasms; Naphthalimides; Phenanthrenes; Phosphorylation; Pyrazoles; Pyrimidines; Signal Transduction

BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.

Topics: A549 Cells; Adoptive Transfer; Animals; Antineoplastic Agents; Bone Morphogenetic Protein Receptors; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Humans; Inhibitor of Differentiation Protein 1; Lung Neoplasms; MAP Kinase Kinase Kinases; Mice; Mice, Inbred NOD; Mice, SCID; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Quinolones; Signal Transduction; Tumor Microenvironment; Xenograft Model Antitumor Assays

RASSF1C is a major isoform of the RASSF1 gene, and is emerging as an oncogene. This is in contradistinction to the RASSF1A isoform, which is an established tumor suppressor. We have previously shown that RASSF1C promotes lung cancer cell proliferation and have identified RASSF1C target genes with growth promoting functions. Here, we further report that RASSF1C promotes lung cancer cell migration and enhances lung cancer cell tumor sphere formation. We also show that RASSF1C over-expression reduces the inhibitory effects of the anti-cancer agent, betulinic acid (BA), on lung cancer cell proliferation. In previous work, we demonstrated that RASSF1C up-regulates piwil1 gene expression, which is a stem cell self-renewal gene that is over-expressed in several human cancers, including lung cancer. Here, we report on the effects of BA on piwil1 gene expression. Cells treated with BA show decreased piwil1 expression. Also, interaction of IGFBP-5 with RASSF1C appears to prevent RASSF1C from up-regulating PIWIL1 protein levels. These findings suggest that IGFBP-5 may be a negative modulator of RASSF1C/ PIWIL1 growth-promoting activities. In addition, we found that inhibition of the ATM-AMPK pathway up-regulates RASSF1C gene expression.

Topics: Antineoplastic Agents; Argonaute Proteins; beta Catenin; Betulinic Acid; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Hydroxamic Acids; Insulin-Like Growth Factor Binding Protein 5; Lung Neoplasms; Pentacyclic Triterpenes; Pyrazoles; Pyrimidines; Signal Transduction; Spheroids, Cellular; Triterpenes; Tumor Suppressor Proteins

Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade.

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Protein Receptors, Type I; Bronchi; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Clone Cells; Endothelial Cells; Epithelial Cells; Gene Knockdown Techniques; Humans; Inhibitor of Differentiation Proteins; Lung Neoplasms; Pyrazoles; Pyrimidines; Signal Transduction; Smad Proteins

Adenosine monophosphate (AMP)-activated kinase (AMPK) is a molecular energy sensor regulated by the tumor suppressor LKB1. Starvation and growth factors activate AMPK through the DNA damage sensor ataxia-telangiectasia mutated (ATM). We explored the regulation of AMPK by ionizing radiation (IR) and its role as a target for radiosensitization of human cancer cells.. Lung, prostate, and breast cancer cells were treated with IR (2-8 Gy) after incubation with either ATM or AMPK inhibitors or the AMPK activator metformin. Then, cells were subjected to either lysis and immunoblotting, immunofluorescence microscopy, clonogenic survival assays, or cell cycle analysis.. IR induced a robust phosphorylation and activation of AMPK in all tumor cells, independent of LKB1. IR activated AMPK first in the nucleus, and this extended later into cytoplasm. The ATM inhibitor KU-55933 blocked IR activation of AMPK. AMPK inhibition with Compound C or anti-AMPK alpha subunit small interfering RNA (siRNA) blocked IR induction of the cell cycle regulators p53 and p21(waf/cip) as well as the IR-induced G2/M arrest. Compound C caused resistance to IR, increasing the surviving fraction after 2 Gy, but the anti-diabetic drug metformin enhanced IR activation of AMPK and lowered the surviving fraction after 2 Gy further.. We provide evidence that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21(waf/cip) and regulation of the cell cycle and survival. AMPK appears to (1) participate in an ATM-AMPK-p21(waf/cip) pathway, (2) be involved in regulation of the IR-induced G2/M checkpoint, and (3) may be targeted by metformin to enhance IR responses.

Topics: AMP-Activated Protein Kinases; Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; DNA-Binding Proteins; Enzyme Activation; Female; G2 Phase; Humans; Lung Neoplasms; Male; Metformin; Morpholines; Phosphorylation; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Pyrones; Radiation Tolerance; RNA, Small Interfering; Tumor Suppressor Protein p53; Tumor Suppressor Proteins