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Lee, Daekee,Yu, Ming,Lee, Eunjung,Kim, Hyunok,Yang, Yanan,Kim, Kyoungmi,Pannicia, Christina,Kurie, Jonathan M.,Threadgill, David W. American Society for Clinical Investigation 2009 The Journal of clinical investigation Vol.119 No.9
<P>Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the ApcMin mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.</P>
Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance
Song, Kwon-Ho,Kim, Jae-Hoon,Lee, Young-Ho,Bae, Hyun Cheol,Lee, Hyo-Jung,Woo, Seon Rang,Oh, Se Jin,Lee, Kyung-Mi,Yee, Cassian,Kim, Bo Wook American Society for Clinical Investigation 2018 The Journal of clinical investigation Vol.128 No.9
<P>The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit ATP5H, which leads to ROS accumulation and HIF-1 alpha stabilization under normoxia. Furthermore, this pathway confers to tumor cells a stem-like and invasive phenotype. In vivo delivery of antioxidants reverses these phenotypic changes and resensitizes tumor cells to therapy. ATP5H loss in the tumor is strongly linked to failure of therapy, disease progression, and poor survival in patients with cancer. Collectively, our results reveal a mechanism underlying immune-driven multimodality resistance to cancer therapy and demonstrate that rational targeting of mitochondrial metabolic reprogramming in tumor cells may overcome this resistance. We believe these results hold important implications for the clinical management of cancer.</P>
Inflammation-associated lymphangiogenesis: a double-edged sword?
Kim, Honsoul,Kataru, Raghu P,Koh, Gou Young American Society for Clinical Investigation 2014 The Journal of clinical investigation Vol.124 No.3
<P>Lymphangiogenesis and lymphatic vessel remodeling are complex biological processes frequently observed during inflammation. Accumulating evidence indicates that inflammation-associated lymphangiogenesis (IAL) is not merely an endpoint event, but actually a phenomenon actively involved in the pathophysiology of various inflammatory disorders. The VEGF-C/VEGFR-3 and VEGF-A/VEGF-R2 signaling pathways are two of the best-studied pathways in IAL. Methods targeting these molecules, such as prolymphangiogenic or antilymphatic treatments, were found to be beneficial in various preclinical and/or clinical studies. This Review focuses on the most recent achievements in the fields of lymphatic biology relevant to inflammatory conditions. Additionally, preclinical and clinical therapies that modulate IAL are summarized.</P>
Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice.
Liu, Tianju,Chung, Myoung Ja,Ullenbruch, Matthew,Yu, Hongfeng,Jin, Hong,Hu, Biao,Choi, Yoon Young,Ishikawa, Fuyuki,Phan, Sem H American Society for Clinical Investigation 2007 The Journal of clinical investigation Vol.117 No.12
<P>In addition to its well-known expression in the germline and in cells of certain cancers, telomerase activity is induced in lung fibrosis, although its role in this process is unknown. To identify the pathogenetic importance of telomerase in lung fibrosis, we examined the effects of telomerase reverse transcriptase (TERT) deficiency in a murine model of pulmonary injury. TERT-deficient mice showed significantly reduced lung fibrosis following bleomycin (BLM) insult. This was accompanied by a significant reduction in expression of lung alpha-SMA, a marker of myofibroblast differentiation. Furthermore, lung fibroblasts isolated from BLM-treated TERT-deficient mice showed significantly decreased proliferation and increased apoptosis rates compared with cells isolated from control mice. Transplantation of WT BM into TERT-deficient mice restored BLM-induced lung telomerase activity and fibrosis to WT levels. Conversely, transplantation of BM from TERT-deficient mice into WT recipients resulted in reduced telomerase activity and fibrosis. These findings suggest that induction of telomerase in injured lungs may be caused by BM-derived cells, which appear to play an important role in pulmonary fibrosis. Moreover, TERT induction is associated with increased survival of lung fibroblasts, which favors the development of fibrosis instead of injury resolution.</P>
Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process
Choi, Jae Young,Khansaheb, Monal,Joo, Nam Soo,Krouse, Mauri E.,Robbins, Robert C.,Weill, David,Wine, Jeffrey J. American Society for Clinical Investigation 2009 The Journal of clinical investigation Vol.119 No.5
<P>Chronic bacterial airway infections are the major cause of mortality in cystic fibrosis (CF). Normal airway defenses include reflex stimulation of submucosal gland mucus secretion by sensory neurons that release substance P (SubP). CFTR is an anion channel involved in fluid secretion and mutated in CF; the role of CFTR in secretions stimulated by SubP is unknown. We used optical methods to measure SubP-mediated secretion from human submucosal glands in lung transplant tissue. Glands from control but not CF subjects responded to mucosal chili oil. Similarly, serosal SubP stimulated secretion in more than 60% of control glands but only 4% of CF glands. Secretion triggered by SubP was synergistic with vasoactive intestinal peptide and/or forskolin but not with carbachol; synergy was absent in CF glands. Pig glands demonstrated a nearly 10-fold greater response to SubP. In 10 of 11 control glands isolated by fine dissection, SubP caused cell volume loss, lumen expansion, and mucus flow, but in 3 of 4 CF glands, it induced lumen narrowing. Thus, in CF, the reduced ability of mucosal irritants to stimulate airway gland secretion via SubP may be another factor that predisposes the airways to infections.</P>
Shimizu, Ippei,Minamino, Tohru,Toko, Haruhiro,Okada, Sho,Ikeda, Hiroyuki,Yasuda, Noritaka,Tateno, Kaoru,Moriya, Junji,Yokoyama, Masataka,Nojima, Aika,Koh, Gou Young,Akazawa, Hiroshi,Shiojima, Ichiro,K American Society for Clinical Investigation 2010 The Journal of clinical investigation Vol.120 No.5
Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15.
Jeon, Young Joo,Jo, Mi Gyeong,Yoo, Hee Min,Hong, Se-Hoon,Park, Jung-Mi,Ka, Seung Hyeun,Oh, Kyu Hee,Seol, Jae Hong,Jung, Yong Keun,Chung, Chin Ha American Society for Clinical Investigation 2012 The Journal of clinical investigation Vol.122 No.7
<P>Identification of the cellular mechanisms that mediate cancer cell chemosensitivity is important for developing new cancer treatment strategies. Several chemotherapeutic drugs increase levels of the posttranslational modifier ISG15, which suggests that ISGylation could suppress oncogenesis. However, how ISGylation of specific target proteins controls tumorigenesis is unknown. Here, we identified proteins that are ISGylated in response to chemotherapy. Treatment of a human mammary epithelial cell line with doxorubicin resulted in ISGylation of the p53 family protein p63. An alternative splice variant of p63, δNp63α, suppressed the transactivity of other p53 family members, and its expression was abnormally elevated in various human epithelial tumors, suggestive of an oncogenic role for this variant. We showed that ISGylation played an essential role in the downregulation of δNp63α. Anticancer drugs, including doxorubicin, induced δNp63α ISGylation and caspase-2 activation, leading to cleavage of ISGylated δNp63α in the nucleus and subsequent release of its inhibitory domain to the cytoplasm. ISGylation ablated the ability of δNp63α to promote anchorage-independent cell growth and tumor formation in vivo as well to suppress the transactivities of proapoptotic p53 family members. These findings establish ISG15 as a tumor suppressor via its conjugation to δNp63α and provide a molecular rationale for therapeutic use of doxorubicin against δNp63α-mediated cancers.</P>