Src/STAT3‐dependent heme oxygenase‐1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy

Abstract

Chemotherapeutic resistance in breast cancer, whether acquired or intrinsic, remains a major clinical obstacle. Thus, increasing tumor cell sensitivity to chemotherapeutic agents will be helpful in improving the clinical management of breast cancer. In the present study, we found an induction of HO-1 expression in doxorubicin (DOX)-treated MDA-MB-231 human breast adenocarcinoma cells, which showed insensitivity to DOX treatment. Knockdown HO-1 expression dramatically upregulated the incidence of MDA-MB-231 cell death under DOX treatment, indicating that HO-1 functions as a critical contributor to drug resistance in MDA-MB-231 cells. We further observed that DOX exposure induced a cytoprotective autophagic flux in MDA-MB-231 cells, which was dependent on HO-1 induction. Moreover, upregulation of HO-1 expression required the activation of both signal transducer and activator of transcription (STAT)3 and its upstream regulator, protein kinase Src. Abrogating Src ⁄ STAT3 pathway activation attenuated HO-1 and autophagy induction, thus increasing the chemosensitivity of MDA-MB-231 cells. Therefore, we conclude that Src ⁄ STAT3-dependent HO-1 induction protects MDA-MB-231 breast cancer cells from DOX-induced death through promoting autophagy. In the following study, we further demonstrated the contribution of Src ⁄ STAT3 ⁄ HO-1 ⁄ autophagy pathway activation to DOX resistance in another breast cancer cell line, MDA-MB-468, which bears a similar phenotype to MDA-MB-231 cells. Therefore, activation of Src ⁄ STAT3 ⁄ HO-1 ⁄ autophagy signaling pathway might play a general role in protecting certain subtypes of breast cancer cells from DOX-induced cytotoxicity. Targeting this signaling event may provide a potential approach for overcoming DOX resistance in breast cancer therapeutics. B reast cancer is the most common malignant disease for Western women.(1) Early detection of breast cancer has improved the prognosis for patients with primary disease confined to the breast but the prognosis for patients with advanced metastatic breast cancer remains poor, which is often due to poor response to standard chemotherapy that is mainly based on anthracyclines and taxanes. Significant advances in the understanding of the mechanisms of anti-cancer drug resistance have not been paralleled by the introduction of novel strategies to circumvent or avoid resistance in clinical practice. Thus, increasing tumor cell sensitivity to these chemotherapeutic agents is an attractive goal towards improving the therapeutic efficacy of breast cancer, and modulation of tumor-specific signaling pathways may provide a different and complementary approach.Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, catalyzes the oxidation of heme to generate several biologically active molecules: carbon monoxide (CO), biliverdin and ferrous ion.(2) Among the three isoforms of the HO family, HO-1 is widely expressed at low levels in most tissues under steady state and is highly inducible under a variety of chemical and physical cellular stresses.(...

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

“…HMOX-1 may be involved in drug resistance of breast cancer cells by preventing apoptosis and autophagy, since siRNA knockdown of HMOX-1 enhanced the cytotoxicity of doxorubicin in MDA-MB-231 and BT549 cells5556. HMOX1 possesses anti-apoptotic activity in imatinib-resistant CML patients57.…”

TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5)

“…The samples were analyzed in the green (FL1) channel of a flow cytometer to obtain the mean fluorescence intensity, as previously described. 40 For the immunoblotting assay, the induction of cellular autophagy in response to PM2.5 exposure was determined as an increase in the endogenous MAP1LC3B-II:LC3B-I ratio, the upregulation of BECN1 expression and the dynamic degradation of SQSTM1. Autophagic flux was assessed by comparing the extent of MAP1LC3B-II accumulation following PM2.5 treatment with or without the concomitant use of BafA1, an inhibitor that prevents autophagosome-lysosome fusion and thereby inhibits autophagic processing and clearance.…”

Heme oxygenase‐1 induction mediates chemoresistance of breast cancer cells to pharmorubicin by promoting autophagy via PI3K/Akt pathway

“…Although surgery, systemic therapy and radiotherapy have been applied for the clinical treatment of breast cancer, these approaches are limited to some extent, because of potential complications or drug resistance . Thus, growing tumour cell sensitivity to chemotherapeutic drugs is an important goal towards enhancing the therapeutic efficacy of breast cancer, and regulation of tumour‐specific signalling is supposed to provide a complementary and different way . In order to explore the molecular functions of autophagy, cell survival as well as drug resistance in breast cancer, this study examined the ability of HO‐1 induction to cell survival and pharmorubicin resistance of breast cancer cells and delineated the connection between PI3K/Akt signalling and autophagy in breast cancer cells to offer evidence for the improvement of breast cancer‐targeted therapies.…”

“…Given that HO‐1 has cytoprotective properties, it has attracted great attention on promoting tumour cell survival in many cancers as followings: increased expression of HO‐1 promoted primary and metastatic prostate tumour growth; Up‐regulating of HO‐1 expression might be effective in controlling cells migration in lung cancer; HO‐1 overexpression could mediate EGF‐induced colon cancer cell proliferation via PI3K/Akt signalling pathway . Furthermore, it was reported that the activation of Src/STAT3/HO‐1/autophagy signalling was supposed to play a crucial role in protecting breast cancer cells from doxorubicin‐induced cytotoxicity . These contrasting observations have undoubtedly increased the significance of HO‐1 in the field of cancer biology.…”