Glutathione S-transferases P1 protects breast cancer cell from adriamycin-induced cell death through promoting autophagy

Abstract

Glutathione S-transferases P1 (GSTP1) is a phase II detoxifying enzyme and increased expression of GSTP1 has been linked with acquired resistance to anti-cancer drugs. However, most anticancer drugs are not good substrates for GSTP1, suggesting that the contribution of GSTP1 to drug resistances might not be dependent on its capacity to detoxify chemicals or drugs. In the current study, we found a novel mechanism by which GSTP1 protects human breast cancer cells from adriamycin (ADR)-induced cell death and contributes to the drug resistance. GSTP1 protein level is very low in human breast cancer cell line MCF-7 but is high in ADR-resistant MCF-7/ADR cells. Under ADR treatment, MCF-7/ADR cells showed a higher autophagy level than MCF-7 cells. Overexpression of GSTP1 in MCF-7 cells by using the DNA transfection vector enhanced autophagy and down-regulation of GSTP1 through RNA interference in MCF-7/ADR cells decreased autophagy. When autophagy was prevented, GSTP1-induced ADR resistance reduced. We found that GSTP1 enhanced autophagy level in MCF-7 cells through interacting with p110α subunit of phosphatidylinositol-3-kinase (PI3K) and then inhibited PI3K/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) activity. Proline123, leucine160, and glutamine163, which located in C terminal of GSTP1, are essential for GSTP1 to interact with p110α, and the following autophagy and drug resistance regulation. Taken together, our findings demonstrate that high level of GSTP1 maintains resistance of breast cancer cells to ADR through promoting autophagy. These new molecular insights provide an important contribution to our better understanding the effect of GSTP1 on the resistance of tumors to chemotherapy.

Integrated Chromatin Accessibility and Transcriptome Landscapes of Doxorubicin-Resistant Breast Cancer Cells

“…It has been reported that overexpression of metallothionein confers resistance to anticancer drugs (Kelley et al, 1988); GPX1 promotes cisplatin resistance via ROS-Induced activation of PI3K/AKT pathway in non-small cell lung cancer (Chen et al, 2019). Up-regulation of GSTP1 maintains resistance to doxorubicin through inhibition of PI3K/AKT/mTOR activity to promote autophagy in breast cancer cells (Dong et al, 2019); Simultaneously, there were a lot of significantly down-regulated genes in MCF7-DR cells, including trefoil factor 1 (TFF1), ubiquitin B (UBB), and SAM pointed domain containing ETS TF (SPDEF). Furthermore, from a perspective of epigenetic regulation, we analyzed the changes in the expression of known histone-modifying enzymes especially.…”

Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma

“…Recent reports have demonstrated that autophagy, induced in response to chemotherapeutic agents, has a crucial influence on the clinical outcome of HCC patients (7)(8)(9). Autophagy is a catabolic mechanism by which cellular material is delivered to lysosomes for degradation, helping cancer cells to maintain homeostasis by recycling the worn-out cellular components (10).…”

Potential Role of GST-π in Lung Cancer Stem Cell Cisplatin Resistance

“…An elevated expression of GST-π is often observed in solid tumor tissues, with GST-π considered as an oncogene essential for the occurrence, metastasis, and drug resistance of cancer [12,13,[22][23][24]. Dong et al [25] demonstrated that high GST-π expression maintained the resistance of breast cancer cells to adriamycin by promoting autophagy. A study of 104 patients with colorectal cancer receiving fluoropyrimidine and platinum-based chemotherapy regimens suggested that the genetic polymorphisms of GST-π were closely associated with chemotherapy effects and adverse reactions, suggesting that GST-π plays a role in the mechanism of action of different types of chemotherapy drugs [26].…”