ANO1, a calcium-activated chloride   channel, is highly expressed and amplified in   human cancers and is a critical survival factor   in these cancers.   We explored the mechanism   behind CaCC  inh  -A01's   inhibitory effect on cell   proliferation using a combined experimental   and in silico approach.   We report that CaCC  inh  -A01 reduces ANO1   protein levels by facilitating endoplasmic   reticulum-associated, proteasomal turnover of   ANO1  . Washout of CaCC  inh  -A01 rescued ANO1  protein levels and resumed cell proliferation.   Proliferation of newly derived CaCC  inh  -A01   resistant cell pools was not affected by CaCC  inh  -  A01 as compared to the parental cells.   Consistently, CaCC  inh  -A01 failed to reduce   ANO1 protein levels in these cells while ANO1-  currents were still inhibited by CaCC  inh  -A01,   indicating that CaCC  inh  -A01 inhibits cell   proliferation by reducing ANO1 protein levels.   Furthermore, we employed in silico methods to   elucidate novel biological functions of ANO1   inhibitors. Specifically, we derived a   pharmacophore model to describe inhibitors   capable of promoting ANO1 degradation and   report new inhibitors of ANO1-dependent cell   proliferation. In summary our data   demonstrate that inhibition of ANO1's channel   activity is not sufficient to inhibit ANO1-   dependent cell proliferation indicating that   ANO1's role in cancer only partially depends on   its function as a channel.

Small molecule facilitated degradation of ANO1 - a new targeting approach for anticancer therapeutics

248th National Meeting (2014)

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