Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death

Emarndeena H Cheteh,Arne Östman,Vladimir Jn Bykov,Julie Bianchi,Klas G Wiman,Victoria Sarne,Martin Augsten,Lars Egevad,Helene Rundqvist

doi:10.1038/cddis.2017.225

Emarndeena H Cheteh, Arne Östman + Show 7 more

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https://doi.org/10.1038/cddis.2017.225

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Abstract

Drug resistance is a major problem in cancer therapy. A growing body of evidence demonstrates that the tumor microenvironment, including cancer-associated fibroblasts (CAFs), can modulate drug sensitivity in tumor cells. We examined the effect of primary human CAFs on p53 induction and cell viability in prostate cancer cells on treatment with chemotherapeutic drugs. Co-culture with prostate CAFs or CAF-conditioned medium attenuated DNA damage and the p53 response to chemotherapeutic drugs and enhanced prostate cancer cell survival. CAF-conditioned medium inhibited the accumulation of doxorubicin, but not taxol, in prostate cancer cells in a manner that was associated with increased cancer cell glutathione levels. A low molecular weight fraction (<3 kDa) of CAF-conditioned medium had the same effect. CAF-conditioned medium also inhibited induction of reactive oxygen species (ROS) in both doxorubicin- and taxol-treated cancer cells. Our findings suggest that CAFs can enhance drug resistance in cancer cells by inhibiting drug accumulation and counteracting drug-induced oxidative stress. This protective mechanism may represent a novel therapeutic target in cancer.

Highlights

Cancer develops by stepwise acquisition of genetic alterations that endow tumor cells with a set of critical properties, including insensitivity to antigrowth signaling, evasion of apoptosis and ability to migrate and form metastasis.[1,2] Tumors can be regarded as complex organs composed of tumor cells and a variety of nonmalignant stromal cells that form the tumor microenvironment
To investigate the effect of prostatic fibroblasts on the survival of prostate cancer cells on treatment with chemotherapeutic drugs, wild-type TP53-carrying LNCaP prostate cancer cells were co-cultured in a transwell system under physical separation with cancer-associated fibroblasts (CAFs) or normal fibroblasts (NFs) from patients
Following culture of LNCaP and primary prostate fibroblasts (CAFs or NFs) in the transwell chamber for 2 to 3 days, the cells were treated with chemotherapeutic drugs (Figure 1a) and LNCaP cell viability was assessed at various time points

Summary

Introduction

Cancer develops by stepwise acquisition of genetic alterations that endow tumor cells with a set of critical properties, including insensitivity to antigrowth signaling, evasion of apoptosis and ability to migrate and form metastasis.[1,2] Tumors can be regarded as complex organs composed of tumor cells and a variety of nonmalignant stromal cells that form the tumor microenvironment. The TP53 gene is frequently mutated in human tumors.[15] The frequency of TP53 mutations in prostate cancer is relatively low, 5–25%, but it is higher in metastatic lesions according to some studies.[16,17,18] In general, tumors that carry mutant TP53 are more resistant to chemotherapy and radiotherapy, consistent with the notion that DNA-damaging drugs and radiotherapy induce tumor cell death at least in part through the activation of wildtype p53 Chemotherapeutic agents such as mitomycin C, taxol and doxorubicin have long been used to treat solid tumors, but development of drug resistance remains a substantial problem. We show that CAFs enhance prostate cancer cell glutathione levels, inhibit drug-induced reactive oxygen species (ROS) and doxorubicin accumulation

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