GSTP1 mediates tumor initiating cell phenotypes and drug resistance in lung cancer

Abstract

Multiple drug resistance is the most important reason for the unsatisfactory outcome of lung cancer treatment. Although tumor initiating cells (TIC) constitute a minority amongst all cancer cell populations, its effects on enhancing tumorigenicity and drug resistance are preponderant. As a Phase II detoxifying enzyme, Glutathione S-transferase pi (GSTP1) catalyzes the conjugation of GSH to substrates such as electrophiles and chemotherapeutic drugs. The role of GSTP1 in chemoresistance has been shown in several types of cancer. However, studies on whether GSTP1 is involved in regulating lung TIC are limited. To address this question, we analyzed data from the TCGA database and a local clinical lung cancer cohort and found GSTP1 expression was significantly up-regulated in lung cancer compared to non-neoplastic lung. Moreover, high expression of GSTP1 significantly correlated with poor patient outcome. We further investigated whether GSTP1 functionally supported TIC by knocking down GSTP1 in lung cancer cells, and observed the ALDH+/CD44+-TIC population was reduced, while in vitro and in vivo self-renewal and tumorigenesis were suppressed. Besides, GSTP1 knockdown significantly inhibited cell mobility and sensitized lung cancer cells to both chemotherapy and target therapy. Reciprocally, by overexpressing GSTP1, both in vitro and in vivo TIC properties were enhanced. To further explore the therapeutic value of GSTP1, we established lung cancer organoids from an excised primary lung adenocarcinoma harboring EML4-ALK translocation. Knocking down GSTP1 significantly suppressed the expression of TIC markers and pluripotency genes in the organoids. Co-treatment using a pharmacological GSTP1 inhibitor significantly sensitized the lung cancer organoids to crizotinib targeted treatment. In summary, these results unveiled the novel functions of GSTP1 in supporting cancer stem cell phenotypes, and indicated GSTP1 might be a promising therapeutic target for lung cancer.