STAT3 inhibition with galiellalactone effectively targets the prostate cancer stem-like cell population

Giacomo Canesin,Anders Bjartell,Anna Stiehm,Rebecka Hellsten,Juan Morote,Enrique A Castellón,Rosanna Paciucci,Valentina Maggio,Hector R Contreras,Macarena Palominos,Norman J Maitland

doi:10.1038/s41598-020-70948-5

Abstract

Cancer stem cells (CSCs) are a small subpopulation of quiescent cells with the potential to differentiate into tumor cells. CSCs are involved in tumor initiation and progression and contribute to treatment failure through their intrinsic resistance to chemo- or radiotherapy, thus representing a substantial concern for cancer treatment. Prostate CSCs’ activity has been shown to be regulated by the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). Here we investigated the effect of galiellalactone (GL), a direct STAT3 inhibitor, on CSCs derived from prostate cancer patients, on docetaxel-resistant spheres with stem cell characteristics, on CSCs obtained from the DU145 cell line in vitro and on DU145 tumors in vivo. We found that GL significantly reduced the viability of docetaxel-resistant and patient-derived spheres. Moreover, CSCs isolated from DU145 cells were sensitive to low concentrations of GL, and the treatment with GL suppressed their viability and their ability to form colonies and spheres. STAT3 inhibition down regulated transcriptional targets of STAT3 in these cells, indicating STAT3 activity in CSCs. Our results indicate that GL can target the prostate stem cell niche in patient-derived cells, in docetaxel-resistant spheres and in an in vitro model. We conclude that GL represents a promising therapeutic approach for prostate cancer patients, as it reduces the viability of prostate cancer-therapy-resistant cells in both CSCs and non-CSC populations.

Highlights

Cancer stem cells (CSCs) are a small subpopulation of quiescent cells with the potential to differentiate into tumor cells
Spheres derived from cancer stem cells (CSCs) (CD133+/ CD44+) showed higher expression of CD133, CD44 and ALDH1A1 (Fig. 1e) as well as higher levels of the Signal Transducer and Activator of Transcription 3 (STAT3)-target genes c-myc, Bcl-XL, Mcl-1 and Survivin compared to spheres derived from transient amplifying/committed basal cells (TA/CB) cells ( CD44+/ CD24+) (Fig. 1f)
In this study we demonstrate that inhibition of activated STAT3 by GL can decrease the viability of docetaxelresistant and patient-derived spheres retaining stemness characteristics, indicating that this is a promising approach to target the cancer stem cell niche in Prostate cancer (PCa)

Summary

Introduction

Cancer stem cells (CSCs) are a small subpopulation of quiescent cells with the potential to differentiate into tumor cells. We investigated the effect of galiellalactone (GL), a direct STAT3 inhibitor, on CSCs derived from prostate cancer patients, on docetaxel-resistant spheres with stem cell characteristics, on CSCs obtained from the DU145 cell line in vitro and on DU145 tumors in vivo. STAT3 inhibition down regulated transcriptional targets of STAT3 in these cells, indicating STAT3 activity in CSCs. Our results indicate that GL can target the prostate stem cell niche in patient-derived cells, in docetaxel-resistant spheres and in an in vitro model. Accumulating evidence indicates that PCa CSCs are characterized by the expression of specific cell surface markers, including CD133 and CD44, and are less differentiated than transient-amplifying (TA) or committed-basal (CB) c ells[10,11,12] These CSCs are able to self-renew and show high clonogenic ability, which makes them key drivers in the oncogenic and metastatic process[13,14]. In this study we investigated the effect of GL on PCa CSCs in several models, including patient-derived primary tumor cultures and docetaxel resistant PCa cell spheres, in order to better characterize this compound as a therapeutic approach for PCa patients

Methods

Results

Conclusion