Metastatic progression, including extravasation and micrometastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1)-induced epithelial-to-mesenchymal transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Overexpressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knockdown was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis.

Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition.

Background: Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin (CLU) gene is a heterodimeric secreted glycoprotein (also termed as sCLU) with a ubiquitous expression in human tissues. CLU exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. Objective: The CLU gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to CLU gene induction, the CLU protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. Conclusion: On the basis of these findings, CLU has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, CLU may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that CLU is a biosensor of oxidative injury; a common link between ageing and all pathologies where CLU has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed.

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The molecular chaperone apolipoprotein J/clusterin as a sensor of oxidative stress: implications in therapeutic approaches - a mini-review.

Ionizing radiation exposure from medical diagnostic imaging has greatly increased over the last few decades. Approximately 80% of patients who undergo medical imaging are exposed to low-dose ionizing radiation (LDIR). Although there is widespread consensus regarding the harmful effects of high doses of radiation, the biological effects of low-linear energy transfer (LET) LDIR is not well understood. LDIR is known to promote oxidative stress, however, these levels may not be large enough to result in genomic mutations. There is emerging evidence that oxidative stress causes heritable modifications via epigenetic mechanisms (DNA methylation, histone modification, noncoding RNA regulation). These epigenetic modifications result in permanent cellular transformations without altering the underlying DNA nucleotide sequence. This review summarizes the major concepts in the field of epigenetics with a focus on the effects of low-LET LDIR (<100 mGy) and oxidative stress on epigenetic gene modification. In this rev...

https://bioone.org/journals/radiation-research/volume-188/issue-4.2/RR14587.1/Low-Dose-Ionizing-Radiation-Exposure-Oxidative-Stress-and-Epigenetic-Programing/10.1667/RR14587.1.pdf

Low-Dose Ionizing Radiation Exposure, Oxidative Stress and Epigenetic Programing of Health and Disease

The cysteine protease CPR-4, a cathepsin B homologue, is identified as a radiation-induced bystander effect (RIBE) factor in nematodes in response to ultraviolet or ionizing radiation, and causes inhibition of cell death and increased embryonic lethality. A possible side-effect of cancer radiotherapy is that irradiated cells or tissues release factors that can affect other tissues and cells that have not been exposed to radiation. This concept, known as radiation-induced bystander effect (RIBE), is well established, but its molecular mediators remain less clear. Studying nematode worms, Ding Xue and colleagues report the identification of an enzyme cysteine protease cathepsin B (CPR-4) as a RIBE factor. They also provide insights into how CPR-4 exerts its effects following secretion in response to exposure of the animals to ultraviolet or ionizing radiation. The protein seems to cause inhibition of cell death and increased embryonic lethality in unexposed parts of the animal through a mechanism that is regulated by the homologue of the tumour suppressor protein p53. The radiation-induced bystander effect (RIBE) refers to a unique process in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses and altered apoptosis or cell proliferation1,2,3. Although RIBEs have important implications for radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain poorly understood. Here we use Caenorhabditis elegans as a model in which to study RIBEs, and identify the cysteine protease CPR-4, a homologue of human cathepsin B, as the first RIBE factor in nematodes, to our knowledge. CPR-4 is secreted from animals irradiated with ultraviolet or ionizing gamma rays, and is the major factor in the conditioned medium that leads to the inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress responses at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by the p53 homologue CEP-1 in response to radiation, and CPR-4 seems to exert RIBEs by acting through the insulin-like growth factor receptor DAF-2. Our study provides crucial insights into RIBEs, and will facilitate the identification of additional RIBE factors and their mechanisms of action.

/pdf/cysteine-protease-cathepsin-b-mediates-radiation-induced-4qxhc47nd8.pdf

Cysteine protease cathepsin B mediates radiation-induced bystander effects

// Cun Wang 1,* , Guangzhi Jin 2,* , Haojie Jin 1,* , Ning Wang 1 , Qin Luo 1 , Yurong Zhang 1 , Dongmei Gao 3 , Kai Jiang 3 , Dishui Gu 1 , Qiujing Shen 1 , Xisong Huo 1 , Fangyuan Hu 1 , Tianxiang Ge 1 , Fangyu Zhao 1 , Wei Chu 1 , Huiqun Shu 1 , Ming Yao 1 , Wenming Cong 2 and Wenxin Qin 1 1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2 Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China 3 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China * These authors contributed equally to this work Correspondence: Wenxin Qin, email: // Wenming Cong, email: // Keywords : Clusterin, hepatocellular carcinoma, metastasis, prognosis, OGX-011 Received : November 16, 2014 Accepted : December 25, 2014 Published : December 30, 2014 Abstract Clusterin (CLU) is a stress-induced chaperone that confers proliferative and survival advantages to cancer cells. However, effects and molecular mechanisms of CLU in hepatocellular carcinoma (HCC) metastasis are still unknown. In this study, HCC tissue array (n = 198) was utilized to investigate correlation between CLU expression and clinicopathological features. Overexpression of CLU in HCC tissues was correlated with shorter overall survival and higher tumor recurrence. In vitro and in vivo assays demonstrated that silencing CLU attenuated the invasion and metastasis of HCC cells, whereas ectopic overexpression of CLU resulted in the forced metastasis of HCC cells. We also revealed that CLU activated Akt signaling through complexing with eukaryotic translation initiation factor 3 subunit I (EIF3I), which in turn promoted matrix metalloproteinase 13 (MMP13) expression and HCC metastasis. Positive correlations between CLU and MMP13, p-Akt, or EIF3I were found in HCC tissues. We further observed that CLU knockdown using the CLU inhibitor OGX-011 significantly suppressed HCC metastasis in two metastatic models through inhibiting EIF3I/Akt/MMP13 signaling. These findings indicate that CLU is an independent predictive factor for prognosis of HCC and it facilitates metastasis through EIF3I/Akt/MMP13 signaling. CLU suppression using OGX-011 may represent a promising therapeutic option for suppressing HCC metastasis.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=3093&path%5B%5D=5973

Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma.

Inadvertent mammalian tissue exposures to low doses of ionizing radiation (IR) after radiation accidents, remediation of radioactive-contaminated areas, space travel or a dirty bomb represent an interesting trauma to an organism. Possible low-dose IR-induced bystander effects could impact our evaluation of human health effects, as cells within tissue are not equally damaged after doses of IR ⩽10 cGy. To understand tissue responses after low IR doses, we generated a reporter system using the human clusterin promoter fused to firefly luciferase (hCLUp-Luc). Secretory clusterin (sCLU), an extracellular molecular chaperone, induced by low doses of cytotoxic agents, clears cell debris. Low-dose IR (⩾2 cGy) exposure induced hCLUp-Luc activity with peak levels at 96 h, consistent with endogenous sCLU levels. As doses increased (⩾1 Gy), sCLU induction amplitudes increased and time-to-peak response decreased. sCLU expression was stimulated by insulin-like growth factor-1, but suppressed by p53. Responses in transgenic hCLUp-Luc reporter mice after low IR doses showed that specific tissues (that is, colon, spleen, mammary, thymus and bone marrow) of female mice induced hCLUp-Luc activity more than male mice after whole body (⩾10 cGy) irradiation. Tissue-specific, non-linear dose- and time-responses of hCLUp-Luc and endogenous sCLU levels were noted. Colon maintained homeostatic balance after 10 cGy. Bone marrow responded with delayed, but prolonged and elevated expression. Intraperitoneal administration of α-transforming growth factor (TGF)β1 (1D11), but not control (13C4) antibodies, immediately following IR exposure abrogated CLU induction responses. Induction in vivo also correlated with Smad signaling by activated TGFβ1 after IR. Mechanistically, media with elevated sCLU levels suppressed signaling, blocked apoptosis and increased survival of TGFβ1-exposed tumor or normal cells. Thus, sCLU is a pro-survival bystander factor that abrogates TGFβ1 signaling and most likely promotes wound healing.

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Low dose IR-induced IGF-1-sCLU expression: A p53-repressed expression cascade that interferes with TGFβ1 signaling to confer a pro-survival bystander effect

David Willson

Papers

Low dose IR-induced IGF-1-sCLU expression: A p53-repressed expression cascade that interferes with TGFβ1 signaling to confer a pro-survival bystander effect