In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3079-3079
Abstract:
Background and Objective: Histone deacetylase (HDAC) inhibitors are clinically proven epigenetic-based drugs for hematological cancers. However, the impact of these inhibitors on solid tumors is disappointing and debatable. Recent studies have shown that the solid tumor cell lines are less sensitive to a HDAC inhibitor Vorinostat (suberoylanilide hydroxamic acid; SAHA) as compared to hematological cell lines. However, it remains elusive why solid tumor cell lines responded weakly to HDAC inhibitors. Previously, it has been reported that CCN1/Cyr61 plays critical role in invasive front and drug resistance in breast and pancreatic cancer. Thus, our goal is to determine whether CCN1 signalling impair activity of SAHA in breast and pancreatic cancer cells. Methods: To test this objective, various breast cancer cell lines (MCF-7, ZR-75-1, MDA-MB-231, HCC-70) and pancreatic cancer cell lines (BxPC-3, AsPC-1 and Panc-1) were treated with SAHA with different does and times. Levels of CCN1 and its downstream signalling molecules were determined in SAHA-treated or untreated cell extracts using Western blotting. In addition, cell viability, migration and sphere formation were examined in parental and CCN1-depleted cells in the presence or absence of SAHA. Results and Conclusions: Here we have shown that CCN1 was upregulated in various breast and pancreatic cancer cell lines following SAHA treatment via epigenetic mechanism. Distribution of CCN1 in the nucleus and cytoplasm was also drastically altered in SAHA-treated cells. Normally, CCN1 expression was detected in the cytoplasm. However, following SAHA treatment, CCN1 expression was located predominantly in the nucleus. Functionally, CCN1 had dual outcome in these cells. The cell viability assay indicated that CCN1-positve breast cancer or pancreatic cancer cells were more sensitive to SAHA as compared to CCN1-negative cells. CCN1 ablation by neutralizing antibody treatment in MDA-MB-231 cells significantly suppressed the inhibitory effect of SAHA in MDA-MB231 cells. However, aggressive phenotype such as migration towards SDF-1 and sphere-formation were markedly elevated in SAHA treated cells as compared to untreated cells. These effects of SAHA were rescued by CCN1-depletion. Collectively, these studies indicat that CCN1 activation limits the response to SAHA in solid tumor cells and thus suggesting that combination therapy of SAHA and CCN1-inhibitor could be an ideal therapeutic approach to make HADAC inhibitor sensitive to solid tumors. Citation Format: Arnab Ghosh, Priyanka Ghosh, Gargi Maity, Sushanta K. Banerjee, Snigdha Banerjee. Activation of CCN1 signaling in solid tumor cells diminishes response to a histone deacetylase inhibitor: A dark side of HDACIs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3079. doi:10.1158/1538-7445.AM2017-3079
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-3079
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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