Dataset Information

Silencing mutated ?-catenin inhibits cell proliferation and stimulates apoptosis in the adrenocortical cancer cell line H295R.

ABSTRACT:

Context

Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm, with limited therapeutic options. Activating ?-catenin somatic mutations are found in ACC and have been associated with a poor clinical outcome. In fact, activation of the Wnt/?-catenin signaling pathway seems to play a major role in ACC aggressiveness, and might, thus, represent a promising therapeutic target.

Objective

Similar to patient tumor specimen the H295 cell line derived from an ACC harbors a natural activating ?-catenin mutation. We herein assess the in vitro and in vivo effect of ?-catenin inactivation using a doxycyclin (dox) inducible shRNA plasmid in H295R adrenocortical cancer cells line (clone named sh?).

Results

Following dox treatment a profound reduction in ?-catenin expression was detectable in sh? clones in comparison to control clones (Ctr). Accordingly, we observed a decrease in Wnt/?catenin-dependent luciferase reporter activity as well as a decreased expression of AXIN2 representing an endogenous ?-catenin target gene. Concomitantly, ?-catenin silencing resulted in a decreased cell proliferation, cell cycle alterations with cell accumulation in the G1 phase and increased apoptosis in vitro. In vivo, on established tumor xenografts in athymic nude mice, 9 days of ?-catenin silencing resulted in a significant reduction of CTNNB1 and AXIN2 expression. Moreover, continous ?-catenin silencing, starting 3 days after tumor cell inoculation, was associated with a complete absence of tumor growth in the sh? group while tumors were present in all animals of the control group.

Conclusion

In summary, these experiments provide evidences that Wnt/?-catenin pathway inhibition in ACC is a promising therapeutic target.

SUBMITTER: Gaujoux S

PROVIDER: S-EPMC3567123 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Silencing mutated β-catenin inhibits cell proliferation and stimulates apoptosis in the adrenocortical cancer cell line H295R.

Gaujoux Sébastien S Hantel Constanze C Launay Pierre P Bonnet Stéphane S Perlemoine Karine K Lefèvre Lucile L Guillaud-Bataille Marine M Beuschlein Felix F Tissier Frédérique F Bertherat Jérôme J Rizk-Rabin Marthe M Ragazzon Bruno B

PloS one 20130207 2

<h4>Context</h4>Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm, with limited therapeutic options. Activating β-catenin somatic mutations are found in ACC and have been associated with a poor clinical outcome. In fact, activation of the Wnt/β-catenin signaling pathway seems to play a major role in ACC aggressiveness, and might, thus, represent a promising therapeutic target.<h4>Objective</h4>Similar to patient tumor specimen the H295 cell line derived from an AC ...[more]

PMID: 23409032

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