In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1034-1034
Abstract:
Nitrogen mustard (HN2) is a chemotherapeutic agent used to treat skin cancers and lymphomas including squamous cell carcinomas (SCC) and cutaneous T cell lymphoma. Although HN2 non-selectively alkylates DNA, many tumors exhibit resistance to HN2 therapy. To evaluate additional mechanisms potentially underlying the activity of HN2 we tested the effects of HN2 on Pam 212 murine squamous cell carcinoma cells. We found that mustard treatment reduced cell viability, and that this result was associated with an increase in PKCδ phosphorylation. Furthermore, cytotoxicity was antagonized by the PKCδ selective inhibitor, rottlerin, implicating this PKC isoform in HN2 action. The p38MAPK inhibitor, SB203580, acted in a similar manner to rottlerin, increasing viability 30% in HN2-treated Pam 212 cells. In contrast, PI3kinase inhibitor, wortmannin, enhanced HN2-mediated cytotoxicity, suggesting a protective role for this signaling pathway. Recent reports indicate that the activity of the p38MAPK and PKCδ signaling cascades, pathways involved in regulating glucose uptake and metabolism, growth, motility, and other essential functions for cell survival, is hallmarked by increases in levels of miRNAs 21 and 183. Therefore we next evaluated the effects of HN2 on microRNA (miR) levels using microRNA PCR arrays. In these experiments we found that HN2 treatment enhanced levels of miR21 and miR183 in Pam 212 keratinocytes, effects that were time and dose-dependent dependent. In additional studies we found that transfection of PAM cells with miR21 and miR183 resulted in enhanced sensitivity to inhibitors of PI3 kinase and p38MAPK regulated mTOR activity. Using techniques in real time PCR we observed that HN2-mediated increases in miRNA 21 and 183 levels were inhibited by the mTOR inhibitors 3-MA, rapamycin and LY294002 in PAM cells. Taken together these data indicate that signaling pathways play significant roles in HN2-mediated inhibition of tumor cell proliferation. We speculate that PKCδ, PI3 kinase, p38MAPK and mTOR pathways are important in the anti-cancer activities of HN2 and may be modified in tumors resistant to this agent. Citation Format: Hong Duck Kim, Michael P. Shakarjian, Anna M. Vetrano, Jeffrey D. Laskin, Diane E. Heck. Induction of miR183 and miR21 is associated with down regulation of cellular signaling in nitrogen mustard mediated inhibition of tumor cell proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1034. doi:10.1158/1538-7445.AM2013-1034
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-1034
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Bookmarklink