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  • American Association for Cancer Research (AACR)  (3)
  • 1
    Online Resource
    Online Resource
    Abstract 2448: Meiosis activating sterols counteract KRas-driven epithelial carcinogenesis via an LXR-dependent mechanism
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2448-2448
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2448-2448
    Abstract: Sterols are structural components of lipid membranes which can exert potent biological activities by regulating cell surface receptor trafficking and stability. Arrest of the sterol pathway at the level of SC4MOL (sterol C4-methyl oxydase-like) or NSDHL (NADPH-dependent steroid dehydrogenase-like) specifically antagonizes signaling and trafficking of the epidermal growth factor receptor (EGFR) (Sukhanova, 2013). SC4MOL and NSDHL catalyze two sequential steps of oxidative decarboxylation of the C4-methyl groups of meiosis activating sterols (MAS). The protein binding MAS has not been identified. We investigated whether the anti-EGFR activities of MAS metabolites are mediated via their interaction with the Liver X Receptor (LXR) so that LXR and its transcriptional targets induce subsequent deregulation of intracellular cholesterol homeostasis. In EGFR-positive carcinoma cell, inhibition of SC4MOL or NSDHL induces upregulation of two canonical LXR targets: the ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1). In keeping with the LXR activation, expression of low density lipoprotein receptor (LDLR) is markedly reduced in SC4MOL or NSDHL-deficient cells. These effects were completely reversible with inactivation of LXR alpha, or via inactivation of an upstream enzyme, CYP51A1, which eliminated MAS. Inactivation of SC4MOL and NSDHL sterol pathway enzymes and upregulation of cholesterol efflux via ABCA1 depleted cholesterol from cellular membranes as evidenced by marked increase of nuclear form of SREBP2. Direct manipulation of SREBP, LXR or LDLR produced concordant synergistic effects with anti-EGFR drugs in carcinoma cell lines suggesting novel combinatorial strategies to treat EGFR-positive carcinomas. In in vivo experiments, SC4MOL or NSDHL-depleted A431 carcinoma xenografts showed exquisite sensitivity to cetuximab. This phenotype was associated with upregulation of LXR target ABCA1 and loss of LDLR. Conditional inactivation of a “floxed” Nsdhl allele via K14-Cre transgene triggered ABCA1 expression in the skin, arrested keratinocytes proliferation and caused lethality in newborn male pups. The anti-proliferative effect of NSDHL deficiency was tested in vivo against KRAS-driven tumors. Skin tumors induced by KRAS in transgenic LSL-KRasG12D mice are EGFR-dependent. Tamoxifen-inducible Tg(K5-CreERTam) mice were crossed with LSL-KRasG12D;NsdhlloxP/loxP and tumors induced by oral tamoxifen administration. Both, NsdhlloxP/Y (NSDHL-null) males carrying only the “floxed” allele and NsdhlloxP/+ heterozygous mosaic females formed skin tumors at similar rate. However, the growth of tumors in NSDHL-null males was completely abrogated. In sum, specific sterol metabolites play a fundamental role in regulating activity of oncogenic EGFR. Inhibition of SC4MOL or NSDHL is a highly effective strategy to counteract oncogenic signaling in carcinomas with activated EGFR-KRAS axis. Citation Format: Linara Gabitova, Andrey Gorin, Diana Restifo, Dong-Hua Yang, David Cunningham, Gail E. Herman, Igor A. Astsaturov. Meiosis activating sterols counteract KRas-driven epithelial carcinogenesis via an LXR-dependent mechanism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2448. doi:10.1158/1538-7445.AM2014-2448
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2448
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Targeting C4-Demethylating Genes in the Cholesterol Pathway Sensitizes Cancer Cells to EGF Receptor Inhibitors via Increased EGF Receptor Degradation
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Discovery Vol. 3, No. 1 ( 2013-01-01), p. 96-111
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 3, No. 1 ( 2013-01-01), p. 96-111
    Abstract: Persistent signaling by the oncogenic EGF receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of 2 sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase–like) and its partner, NSDHL (NADP-dependent steroid dehydrogenase–like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa1H/+ mice confirmed dramatic and selective loss of internalized platelet-derived growth factor receptor in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL. Significance: This work identifies a critical role for SC4MOL and NSDHL in the regulation of EGFR signaling and endocytic trafficking and suggests novel strategies to increase the potency of EGFR antagonists in tumors. Cancer Discov; 3(1); 96–111. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-12-0031
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2607892-2
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  • 3
    Online Resource
    Online Resource
    MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 20 ( 2022-10-14), p. 4456-4465
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 20 ( 2022-10-14), p. 4456-4465
    Abstract: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC). Experimental Design: Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. Results: Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation. Conclusions: This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-4183
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 2036787-9
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