Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells

Emarndeena H Cheteh; Victoria Sarne; Sophia Ceder; Julie Bianchi; Martin Augsten; Helene Rundqvist; Lars Egevad; Arne Östman; Klas G Wiman

doi:10.1038/s41420-020-0272-5

Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells

Cell Death Discov. 2020 Jun 2:6:42. doi: 10.1038/s41420-020-0272-5. eCollection 2020.

Authors

Emarndeena H Cheteh¹, Victoria Sarne², Sophia Ceder¹, Julie Bianchi¹, Martin Augsten¹, Helene Rundqvist³, Lars Egevad¹, Arne Östman¹, Klas G Wiman¹

Affiliations

¹ Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
² Department of Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
³ Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Abstract

Cancer-associated fibroblasts (CAFs) promote tumor growth and progression, and increase drug resistance through several mechanisms. We have investigated the effect of CAFs on the p53 response to doxorubicin in prostate cancer cells. We show that CAFs produce interleukin-6 (IL-6), and that IL-6 attenuates p53 induction and upregulation of the pro-apoptotic p53 target Bax upon treatment with doxorubicin. This is associated with increased levels of MDM2 mRNA, Mdm2 protein bound to p53, and ubiquitinated p53. IL-6 also inhibited doxorubicin-induced cell death. Inhibition of JAK or STAT3 alleviated this effect, indicating that IL-6 attenuates p53 via the JAK/STAT signaling pathway. These results suggest that CAF-derived IL-6 plays an important role in protecting cancer cells from chemotherapy and that inhibition of IL-6 could have significant therapeutic value.

Keywords: Cancer microenvironment; Cancer therapeutic resistance; Tumour-suppressor proteins.