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Fig. 10 | Journal of Experimental & Clinical Cancer Research

Fig. 10

From: Increasing intratumor C/EBP-β LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer

Fig. 10

Proposed molecular circuitries linking C/EBP-β LIP, NO and Pgp in breast cancer. Breast cancer doxorubicin-sensitive cells have high C/EBP-β LIP/CHOP/TRB3/caspase 3-axis, low expression of P-glycoprotein (Pgp) and high expression of calreticulin, consequent to the high C/EBP-β LIP levels. In these cells, doxorubicin (DOX) reaches intracellular concentrations sufficient to induce ER stress-dependent cell death and immunogenic cell death. By contrast, doxorubicin-resistant cells have high lysosome and proteasome activities that down-regulates C/EBP-β LIP, prevent the activation of C/EBP-β LIP/CHOP/TRB3/caspase 3-axis, decreases calreticulin expression and nitric oxide (NO) production. These events determine high expression and activity of Pgp and abrogate the efficacy of doxorubicin. The combined inhibition (I) of lysosome and proteasome with chloroquine (CQ) and bortezomib (B) restores the C/EBP-β LIP/CHOP/TRB3/caspase 3-axis and the synthesis of NO, lowering expression and activity of Pgp, increasing transcription and translocation to the plasma-membrane of calreticulin. This rewiring restores the mechanisms of doxorubicin’s induced cell death via ER stress and immunogenic cell death, overcoming drug resistance in vitro and in vivo

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