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.