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KCNN4 induces multiple chemoresistance in breast cancer by regulating BCL2A1.

ABSTRACT: Multidrug chemoresistance is a major clinical obstacle in breast cancer treatment. We aimed to elucidate the sensitivity to therapeutics in gemcitabine-resistant breast cancer models. Pooled library screening combined with RNA-seq was conducted to explore the potential targets involved in gemcitabine resistance in breast cancer cells. Cytotoxicity and tumor xenograft assays were used to evaluate the effect of calcium-activated channel subfamily N member 4 (KCNN4) inhibitors on the cellular sensitivity of breast cancer cells to chemotherapeutic drugs both in vitro and in vivo. We found that KCNN4 is an important determinant for the cytotoxicity of gemcitabine. Elevated KCNN4 expression enhanced resistance to chemotherapeutic antimetabolites and promoted cell proliferation. Conversely, silencing KCNN4 or chemical inhibition of KCNN4 by the specific inhibitor TRAM-34 inhibited the chemoresistance and cell proliferation. Mechanistically, KCNN4 upregulated BCL2-related protein A1 (BCL2A1) to suppress apoptosis by activating RAS-MAPK and PI3K-AKT signaling. Moreover, high expression levels of KCNN4 and BCL2A1 were associated with shortened disease-free survival in the cohort studies. Collectively, our findings showed that KCNN4 is a key modulator of progression and drug resistance in breast cancer, indicating that targeting KCNN4 may serve as a promising therapeutic strategy to overcome multidrug chemoresistance in this disease.

SUBMITTER: Lin P

PROVIDER: S-EPMC7642670 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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KCNN4 induces multiple chemoresistance in breast cancer by regulating BCL2A1.

Lin Peiyang P Li Junjing J Ye Fugui F Fu Wenfen W Hu Xin X Shao Zhiming Z Song Chuangui C

American journal of cancer research 20201001 10

Multidrug chemoresistance is a major clinical obstacle in breast cancer treatment. We aimed to elucidate the sensitivity to therapeutics in gemcitabine-resistant breast cancer models. Pooled library screening combined with RNA-seq was conducted to explore the potential targets involved in gemcitabine resistance in breast cancer cells. Cytotoxicity and tumor xenograft assays were used to evaluate the effect of calcium-activated channel subfamily N member 4 (KCNN4) inhibitors on the cellular sensi ...[more]

PMID: 33163271

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Project description:Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 (gal-7) was recently shown to be specifically expressed in basal-like but not in luminal subtypes of human breast cancer.We generated a mutant form of gal-7 (R74S). Arginine 74 is the structural equivalent of arginine 186 found in human galectin-3. Mutation R186S was previously shown to abolish the biological function of galectin-3.Mutation of arginine 74 induced only limited and local changes to the gal-7 fold. Recombinant forms of R74S and wtgal-7 were also equally effective at forming dimers in solution. Analysis of the thermodynamic parameters by isothermal titration calorimetry (ITC) indicated, however, that binding of lactose to gal-7 was inhibited by the R74S mutation. Using confocal microscopy and electron microscopy, we confirmed the expression of gal-7 in the cytosolic and nuclear compartments of breast cancer cells and the ability of gal-7 to translocate to mitochondria. The mutation at position 74, however, greatly reduced the expression of gal-7 in the nuclear and mitochondrial compartments. Interestingly, cells expressing mutated gal-7 were equally if not even more resistant to drug-induced apoptosis when compared to cells expressing wtgal-7. We also found that both wtgal-7 and R74S inhibited dox-induced PARP-1 cleavage and p53 protein expression. The inhibition of p53 correlated with a decrease in p21 protein expression and CDKN1A mRNA. Furthermore, analysis of nuclear and cytoplasmic fractions showed that both wild type and R74S mutant gal-7 inhibited p53 nuclear translocation, possibly by increasing degradation of cytosolic p53.These findings pose a challenge to the paradigm that has guided the design of galectin-specific inhibitors for the treatment of cancer. This study suggests that targeting CRD-independent cytosolic gal-7 in breast cancer cells may be a valuable strategy for the treatment of this disease. Our study will thus complement efforts towards improving selectivity of targeted anticancer agents.

Dataset Information

KCNN4 induces multiple chemoresistance in breast cancer by regulating BCL2A1.

Publications

KCNN4 induces multiple chemoresistance in breast cancer by regulating BCL2A1.

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