• Colorectal cancer (CRC)
• Epigenetics
• Histone deacetylases
• SIRT1

• Humans
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/drug therapy
• Sirtuin 1/metabolism
• Animals
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Cell Proliferation
• Apoptosis
• Epigenesis, Genetic

• SIRT1
• apoptosis
• cancer
• deacetylates
• p53

• Inauhzin
• anticancer
• calcium
• casein kinase
• eryptosis
• hemolysis
• oxidative stress

Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking is the most common risk factor for lung carcinoma; other risks include genetic factors and exposure to radon gas, asbestos, secondhand smoke, and air pollution. Nicotine, the primary addictive constituent of cigarettes, contributes to cancer progression through activation of nicotinic acetylcholine receptors (nAChRs), which are membrane ligand-gated ion channels. Activation of nicotine/nAChR signaling is associated with lung cancer risk and drug resistance. We focused on nAChR pathways activated by nicotine and its downstream signaling involved in regulating apoptotic factors of mitochondria and drug resistance in lung cancer. Increasing evidence suggests that several sirtuins play a critical role in multiple aspects of cancer drug resistance. Thus, understanding the consequences of crosstalk between nicotine/nAChRs and sirtuin signaling pathways in the regulation of drug resistance could be a critical implication for cancer therapy.

• drug resistance
• lung cancer
• mitochondria
• nicotinic acetylcholine receptor
• sirtuin

• chemosensitivity
• lung adenocarcinoma cell
• tumor protein p53α gene

• Drug discovery
• Inauhzin
• MDM2
• MDMX
• Small molecules
• p53

• SIRT1
• apoptosis
• chlorpromazine
• drug reposition
• p53

Increasing evidence highlights the important roles of microRNAs in mediating p53’s tumor suppression functions. Here, we report miR-139-5p as another new p53 microRNA target. p53 induced the transcription of miR-139-5p, which in turn suppressed the protein levels of phosphodiesterase 4D (PDE4D), an oncogenic protein involved in multiple tumor promoting processes. Knockdown of p53 reversed these effects. Also, overexpression of miR-139-5p decreased PDE4D levels and increased cellular cAMP levels, leading to BIM-mediated cell growth arrest. Furthermore, our analysis of human colorectal tumor specimens revealed significant inverse correlation between the expression of miR-139-5p and that of PDE4D. Finally, overexpression of miR-139-5p suppressed the growth of xenograft tumors, accompanied by decrease in PDE4D and increase in BIM. These results demonstrate that p53 inactivates oncogenic PDE4D by inducing the expression of miR-139-5p.

DOI:http://dx.doi.org/10.7554/eLife.15978.001

The human body is kept mostly free from tumors by the actions of so-called tumor suppressor genes. One such gene encodes a protein called p53, which prevents tumors from growing by regulating the activity of many other genes that either inhibit cell growth or cause cells to die. For example, p53 regulates genes that encode short molecules called microRNAs, which in turn suppress the activity of other target genes.

Although a number of microRNAs have been reported as p53-regulated genes, there are still more to find. Discovering these genes would in turn help researchers to better understand exactly how p53 acts to suppress the growth of tumors, and to treat cancers caused by mutations in this tumor suppressor gene.

Cao, Wang et al. now discover a new microRNA – called miR-139-5p – as one that is activated by p53 in human cells. Colon tumors produce much lower levels of this microRNA than normal tissues, while the cancer cells with a higher level of miR-139-5p grow slower than do the cancer cells with less miR-139-5p. Further experiments showed that this is because miR-139-5p can suppress the production of a protein called PDE4D, which is often highly expressed in human cancers. The suppression of PDE4D by this microRNA results in an increase in the levels of a protein that can cause cancer cells to die.

Cao, Wang et al. suggest that miR-139-5p and PDE4D form part of a signaling pathway that plays an important role in suppressing the growth of colon cancer cells. Since microRNAs often have more than one target, future studies could explore if miR-139-5p regulates the production of other cancer-related proteins as well.

DOI:http://dx.doi.org/10.7554/eLife.15978.002

• BIM
• PDE4D
• apoptosis
• cancer biology
• human
• miR-139-5p
• mouse
• p53
• tumor suppression

• Dox, doxorubicin
• FACS, Fluorescence-activated cell sorting
• GTP, guanosine triphosphate
• INZ, inauhzin
• Inauhzin
• MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
• PBS, Phosphate Buffered Saline
• PI, propidium iodide
• RISC, RNA-induced silencing complex
• RP, ribosomal protein
• RPL11
• RPL5
• UTR, untranslated region
• c-Myc
• lymphoma
• microRNA
• q-RT-PCR, Real-time reverse transcription polymerase chain reaction

• Chemotherapy
• Intrinsic cancer resistance
• Pets
• Proton pump inhibitors
• Tumor acidity

• lung cancer
• malignant pleural effusion
• pleurodesis

Reactivating the tumor suppressor p53 offers an attractive strategy for developing cancer therapy. We recently identified Inauhzin (INZ) as a novel non-genotoxic p53-activating compound. To develop INZ into a clinically applicable anticancer drug, we have initiated preclinical toxicity studies. Here, we report our study on determining the maximum tolerated dose (MTD) of INZ analog, Inauhzin-C (INZ (C)), following intraperitoneal (i.p.) administration (Phase A) and its toxicity following i.p. administration over a period of 5-day dosing plus 2-day recovery (Phase B) in CD-1 mice. The Phase A study showed that the MTD of INZ (C) is 200 mg/kg for female and 250 mg/kg for male, respectively. The Phase B study showed that the administration of INZ (C) via 5-day consecutive i.p. injection is tolerated by female CD-1 mice at all dose levels tested from 50 mg/kg to 120 mg/kg without significant changes in biochemical and pathological parameters in the animals. Together, these results indicate that our previously determined effective dose of INZ at 30–60 mg/kg via i.p. is quite safe to mice, and imply that this compound have the features worthy for further development into a clinically applicable drug.

• Inauhzin
• dose range finding
• maximum tolerated dose
• mouse
• toxicity study

• IMPDH2
• Inauhzin
• MDM2
• cell biology
• human
• nucleostemin
• p53
• ribosomal stress