A major goal of cancer research is the identification of tumor-specific vulnerabilities that can be exploited for the development of therapies that are selectively toxic to the tumor. We show here that the transcriptional coactivators peroxisome proliferatoractivated receptor gamma coactivator 1 (PGC1) and estrogen-related receptor ␣ (ERR␣) are aberrantly expressed in human colon cell lines and tumors. With kinase suppressor of Ras 1 (KSR1) depletion as a reference standard, we used functional signature ontology (FUSION) analysis to identify the ␥1 subunit of AMP-activated protein kinase (AMPK) as an essential contributor to PGC1 expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (␣22␥1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1. In contrast, PGC1 and ERR␣ are not detectable in nontransformed human colon epithelial cells, and depletion of the AMPK␥1 subunit has no effect on their viability. These data indicate that Ras oncogenesis relies on the aberrant activation of a PGC1-dependent transcriptional pathway via a specific AMPK isoform.A third of all human cancers, including a substantial percentage of colorectal, lung, and pancreatic cancers, are driven by activating mutations in Ras genes. Activating K-Ras mutations are present in 35 to 40% of colon tumors and are thought to be both drivers of tumorigenesis and determinants of therapeutic regimens (1). Therapeutic disruption of Ras function has been clinically ineffective to date, but investigation of Ras pleiotropy continues to yield a diversity of downstream effectors with obligate roles in the maintenance and adaptation of Ras-driven tumors to changing environments. The Raf-MEK-extracellular signal-regulated kinase (ERK) signaling pathway is essential for the oncogenic properties of mutated K-Ras (2). However, numerous potent and specific MEK inhibitors have been developed yet have failed to demonstrate single-agent efficacy in cancer treatment (3). As a molecular scaffold of the Raf-MEK-ERK kinase cascade (4, 5), kinase suppressor of Ras 1 (KSR1) is necessary and sufficient for Ras V12 -induced tumorigenesis (4), mouse embryo fibroblast (MEF) transformation (5, 6), and pancreatic cancer growth (7) but dispensable for normal development (4). KSR1 is overexpressed in endometrial carcinoma and is required for both proliferation and anchorage-independent growth of endometrial cancer cells (8). Except for minor defects in hair follicles, KSR1 knockout mice are fertile and develop normally (4).This observation predicts that small molecules targeting KSR1 and functionally related effectors should preferentially target Rasdriven tumors while leaving normal tissue largely unaffected. More generally, this observation demonstrates that tumor cells, while under selective pressure to adapt to inhospitable environments and proliferate without constraint, will adopt strategies that, while advantageous to that singular purpose, create...
Kinase suppressor of ras 1 (KSR1) is a molecular scaffold of the Raf/MEK/extracellular signal-regulated kinase (ERK) cascade that enhances oncogenic Ras signaling. Here we show KSR1-dependent, but ERKindependent, regulation of metabolic capacity is mediated through the expression of peroxisome proliferatoractivated receptor gamma coactivator 1␣ (PGC1␣) and estrogen-related receptor ␣ (ERR␣). This KSR1-regulated pathway is essential for the transformation of cells by oncogenic Ras. In mouse embryo fibroblasts (MEFs) expressing H-Ras V12 , ectopic PGC1␣ was sufficient to rescue ERR␣ expression, metabolic capacity, and anchorage-independent growth in the absence of KSR1. The ability of PGC1␣ to promote anchorageindependent growth required interaction with ERR␣, and treatment with an inhibitor of ERR␣ impeded anchorage-independent growth. In contrast to PGC1␣, the expression of constitutively active ERR␣ (CA-ERR␣) was sufficient to enhance metabolic capacity but not anchorage-independent growth in the absence of KSR1. These data reveal KSR1-dependent control of PGC1␣-and ERR␣-dependent pathways that are necessary and sufficient for signaling by oncogenic H-Ras V12 to regulate metabolism and anchorage-independent growth, providing novel targets for therapeutic intervention.
AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA-mediated depletion induces cell death. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. We used Functional Signature Ontology (FUSION) to screen a natural product library to identify compounds that were inhibitors of AMPK to test its potential for detecting small molecules with preferential toxicity toward human colon tumor cells. FUSION identified 5′-hydroxy-staurosporine, which competitively inhibits AMPK. Human colon cancer cell lines are notably more sensitive to 5′-hydroxy-staurosporine than are non-transformed human colon epithelial cells. This study serves as proof-of-concept for unbiased FUSION-based detection of small molecule inhibitors of therapeutic targets and highlights its potential to identify novel compounds for cancer therapy development.
improvement in drug response and reduction of toxicity were observed after continuous intrahepatic arterial infusion of mytomycin-C (MMC) and 5-fluorouracil (5-FU) in 15 of 26 patients with primary or metastatic carcinoma of the liver. Serum bilirubin values of 10 mg/100 ml absence of ascites, extreme cachexia and impending hepatic failure were used as the criteria for admission of these patients into the study. The patients were given MMC in a dose of 0.08 mg/kgon day 1,5-FUin a dose of8-10 mg/kgon days2-5,and MMCon day6. This schedule was reinitiated on days 8 and 15 for a total mean duration of 18 days. Maintenance therapy was carried out by the administration of these drugs at induction dosage alternated each week as a single 24 hourly intravenous infusion. Objective response to combination therapy was defined as decrease of at least 50% in the liver size and in the abnormal levels of serum alkaline phosphatase and glutamic oxaloacetic transaminase (SGOT) , and near normal levels of serum bilirubin for a minimum period of 2 months. The duration of objective response ranged from 3-16 months with a median of8.2 months. The median survival time for the responders was 7.2 months for patients with primary carcinoma and 9.4 months for patients with metastatic carcinoma of the liver as compared to 2 months for patients who failed to respond to the treatment. Five out of 12 patients who were refractory to MMC or 5-FU by intravenous infusion responded to the present combination drug therapy. Of four patients who died during induction therapy, three had liver failure and the fourth suffered pulmonary embolism. These studies provide evidence that combination therapy with MMC and 5-FU increases the survival time of patients with hepatic cancer, presumably due to the synergistic action of these drugs which permits the use of a low dosage schedule and has less toxic effects.Cancer 39:1425-1429, 1977. shown to be effective individually in primary and metastatic hepatic tumors. Earlier studies have indicated synergistic effects of the combination of MMC and 5-FU by inhibition of the murine Sa-180 and ascitic leukemia, L-1210. l9 I n our investigations the use of combination therapy with MMC and 5-FU by intra-arterial infusion was found effective in the treatment of patients with advanced oral carcinoma. These observations prompted a prospective study to evaluate the chemotherapeutic effectiveness of intrahepatic arterial infusion of MMC and 5-FU in patients with primary and metastatic carcinoma of the liver. NTRAHEPATIC ARTERIAL INFUSION T H E R
We have probed the changes in the phonon and magnon modes of BiFeO3 on substitution of Ba and Ca at the A-site using infrared reflectance spectroscopy. The systematic hardening of the phonon modes in the doped samples is seen to correlate well with the volume reduction of the unit cell observed from the Rietveld measurements. This is attributed to the generation of chemical pressure in these samples on account of substitution of the dopants. In addition, a near-complete suppression accompanied by a complete lifting of the degeneracy of the magnon modes as compared to the pristine BiFeO3 is detected for the Ca-doped samples. These results suggest that aliovalent doping at A-site affects the crystal field of FeO6 octahedra of BiFeO3, which eventually modifies its magnetic nature. These doping-induced modifications are mainly responsible for the improved magnetic and magnetoelectric properties of the Ca-doped BiFeO3 samples.
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