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Molecular Cancer Research Research Article A Modified HSP70 Inhibitor Shows Broad Activity as an Anticancer Agent Gregor M. Balaburski, Julia I.-Ju Leu, Neil Beeharry, Seth Hayik, Mark D. Andrake, Gao Zhang, Meenhard Herlyn, Jessie Villanueva, Roland L. Dunbrack, Tim Yen, Donna L. George, and Maureen E. Murphy Maureen E. Murphy Abstract The stress-induced HSP70 is an ATP-dependent molecular chaperone that plays a key role in refolding misfolded proteins and promoting cell survival following stress. HSP70 is marginally expressed in nontransformed cells, but is greatly overexpressed in tumor cells. Silencing HSP70 is uniformly cytotoxic to tumor but not normal cells; therefore, there has been great interest in the development of HSP70 inhibitors for cancer therapy. Here, we report that the HSP70 inhibitor 2-phenylethynesulfonamide (PES) binds to the substrate-binding domain of HSP70 and requires the C-terminal helical “lid” of this protein (amino acids 573–616) to bind. Using molecular modeling and in silico docking, we have identified a candidate binding site for PES in this region of HSP70, and we identify point mutants that fail to interact with PES. A preliminary structure–activity relationship analysis has revealed a derivative of PES, 2-(3-chlorophenyl) ethynesulfonamide (PES- Cl), which shows increased cytotoxicity and ability to inhibit autophagy, along with significantly improved ability to extend the life of mice with pre-B-cell lymphoma, compared with the parent compound (P = 0.015). Interestingly, we also show that these HSP70 inhibitors impair the activity of the anaphase promoting complex/cyclosome (APC/C) in cell-free extracts, and induce G 2 –M arrest and genomic instability in cancer cells. PES- Cl is thus a promising new anticancer compound with several notable mechanisms of action. Mol Cancer Res; 11(3); 219–29. ©2013 AACR. Mol Cancer Res March 2013 11:219–229; Published OnlineFirst January 9, 2013; doi:10.1158/1541-7786.MCR-12-0547-T Research Article The Heterochronic microRNA let-7 Inhibits Cell Motility by Regulating the Genes in the Actin Cytoskeleton Pathway in Breast Cancer Xiaowen Hu, Jinyi Guo, Lan Zheng, Chunsheng Li, Tim M. Zheng, Janos L. Tanyi, Shun Liang, Chiara Benedetto, Marco Mitidieri, Dionyssios Katsaros, Xia Zhao, Youcheng Zhang, Qihong Huang, and Lin Zhang Lin Zhang Abstract The heterochronic gene let-7 serves as a tumor suppressor microRNA by targeting various oncogenic pathways in cancer cells. Considerable evidence indicates that reduced expression of let-7 might be associated with poor clinical outcome in patients with cancer. Here, we report that the expression levels of three let-7 family members, let-7a, let-7b, and let-7g, were significantly decreased in the patients with breast cancer with lymph node metastasis compared with those without lymph node metastasis. Enforced expression of let-7b significantly inhibits breast cancer cell motility and affects actin dynamics. Using bioinformatic and experimental approaches, four genes in the actin cytoskeleton pathway, including PAK1, DIAPH2, RDX, and ITGB8, were identified as let-7 direct targets. Blocking the expression of PAK1, DIAPH2, and RDX significantly inhibits breast cancer cell migration induced by let-7b repression. Our results indicate that reconstitution of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of metastatic disease. Mol Cancer Res; 11(3); 240–50. ©2013 AACR. Mol Cancer Res March 2013 11:240–250; Published OnlineFirst January 21, 2013; doi:10.1158/1541-7786.MCR-12-0432 20 aacrjournals.org
Molecular Cancer Research Research Article Procollagen Lysyl Hydroxylase 2 Is Essential for Hypoxia-Induced Breast Cancer Metastasis Daniele M. Gilkes, Saumendra Bajpai, Carmen C. Wong, Pallavi Chaturvedi, Maimon E. Hubbi, Denis Wirtz, and Gregg L. Semenza Gregg L. Semenza Abstract Metastasis is the leading cause of death among patients who have breast cancer. Understanding the role of the extracellular matrix (ECM) in the metastatic process may lead to the development of improved therapies to treat patients with cancer. Intratumoral hypoxia, found in the majority of breast cancers, is associated with an increased risk of metastasis and mortality. We found that in hypoxic breast cancer cells, hypoxia-inducible factor 1 (HIF-1) activates transcription of the PLOD1 and PLOD2 genes encoding procollagen lysyl hydroxylases that are required for the biogenesis of collagen, which is a major constituent of the ECM. High PLOD2 expression in breast cancer biopsies is associated with increased risk of mortality. We show that PLOD2 is critical for fibrillar collagen formation by breast cancer cells, increases tumor stiffness, and is required for metastasis to lymph nodes and lungs. Mol Cancer Res; 11(5); 456–66. ©2013 AACR. Mol Cancer Res May 2013 11:456–466; Published OnlineFirst February 1, 2013; doi:10.1158/1541-7786.MCR-12-0629 Research Article Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC Hideki Terai, Kenzo Soejima, Hiroyuki Yasuda, Sohei Nakayama, Junko Hamamoto, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Shinnosuke Ikemura, Takashi Sato, Satoshi Yoda, Ryosuke Satomi, Katsuhiko Naoki, and Tomoko Betsuyaku Kenzo Soejima Abstract Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2-FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2-FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs. Mol Cancer Res; 11(7); 759–67. ©2013 AACR. Mol Cancer Res July 2013 11:759–767; Published OnlineFirst March 27, 2013; doi:10.1158/1541-7786.MCR-12-0652 The Best of the AACR Journals 21
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