Blocking the functional domain of TIP1 by antibodies sensitizes cancer to radiation therapy.

Non-small-cell lung cancer (NSCLC) and glioblastoma (GB) have poor prognoses. Discovery of new molecular targets is needed to improve therapy. Tax interacting protein 1 (TIP1), which plays a role in cancer progression, is overexpressed and radiation-inducible in NSCLC and GB. We evaluated the effect of an anti-TIP1 antibody alone and in combination with ionizing radiation (XRT) on NSCLC and GB in vitro and in vivo. NSCLC and GB cells were treated with anti-TIP1 antibodies and evaluated for proliferation, colony formation, endocytosis, and cell death. The efficacy of anti-TIP1 antibodies in combination with XRT on tumor growth was measured in mouse models of NSCLC and GB. mRNA sequencing was performed to understand the molecular mechanisms involved in the action of anti-TIP1 antibodies. We found that targeting the functional domain of TIP1 leads to endocytosis of the anti-TIP1 antibody followed by reduced proliferation and increased apoptosis-mediated cell death. Anti-TIP1 antibodies bound specifically (with high affinity) to cancer cells and synergized with XRT to significantly increase cytotoxicity in vitro and reduce tumor growth in mouse models of NSCLC and GB. Importantly, downregulation of cancer survival signaling pathways was found in vitro and in vivo following treatment with anti-TIP1 antibodies. TIP1 is a new therapeutic target for cancer treatment. Antibodies targeting the functional domain of TIP1 exhibited antitumor activity and enhanced the efficacy of radiation both in vitro and in vivo. Anti-TIP1 antibodies interrupt TIP1 function and are effective cancer therapy alone or in combination with XRT in mouse models of human cancer.

Organochlorine pesticides induce epithelial as well as inflammatory mediators following exposure to human ovarian surface epithelial cells: An in vitro study.

Although studies have suggested organochlorine pesticides (OCPs) exposure increased the risk of epithelial ovarian cancer, the mechanisms underlying its potential tumorigenic effects in the human ovary are not well understood. In this study, we investigated the impact of dichlorodiphenyldichloroethylene (DDE), endosulfan, and heptachlor exposure on epithelial cadherin (E-cadherin) and proinflammatory mediators in human ovary surface epithelial (HOSE) cells. We found that DDE, endosulfan, and heptachlor exposure resulted in epithelial differentiation accompanied by upregulation of E-cadherin expression and overexpression of proinflammatory cytokines (TNFα, IL-1ß, and IL-6) in HOSE cells. The epithelial differentiation may accelerate HOSE cells to inclusion body formation, a common site for ovarian cancer initiation and persistent exposure to OCPs creates a chronic inflammatory microenvironment that may promote the neoplastic transformation of HOSE cells within the inclusion cyst.

Delineating Potential Transcriptomic Association with Organochlorine Pesticides in the Etiology of Epithelial Ovarian Cancer.

BACKGROUND: Recent studies have shown that there is an increased risk of Epithelial Ovarian Cancer (EOC) with Organochlorine Pesticides (OCPs). However, the alteration in the gene expression profile has not been explored so far. The goal of the present study is to understand the probable molecular mechanism of OCPs toxicity towards discovery of dysregulation of signaling pathway associated with differential gene expression and candidate transcriptomic set of markers in the pathophysiology of EOC in OCPs exposed population. METHODS: The OCP levels were estimated by gas chromatography and whole genome differential expression study was carried out using expression microarray and candidate genes were validated using Real time RT-PCR. RESULTS: Significant level of OCP residues such as ß-hexachlorocyclohexane (ß-HCH), Heptachlor, Heptachlor epoxide B (HTEB), dichlorodiphenyldichloroethylene (p'p'-DDE) and endosulfan-I was found between healthy and EOC patients. The transcriptome profile of several genes revealed regulation of various important cellular processes such as metabolism, inflammation, cytoskeleton dysregulation of TGF and WNT pathway in EOC cases with high OCPs. CONCLUSION: This study provides the first evidence showing that differentially expressed genes and dysregulation of signaling pathways might be associated with significant level of OCPs exposure in ovary tissue of epithelial ovarian cancer patients. Moreover, significant correlation of these genes with OCPs revealed that OCPs exposure played vital role in dysregulation of related pathways in the etiology of EOC.