p53 and cancer-associated fibroblasts : implications for cancer therapy and drug resistance

Sammanfattning: Drug resistance remains as a major problem and a daunting challenge to successful anticancer treatment. Cancer cells are masters of adaptation. Novel drugs that attack cancer in new ways and target key drivers of cancer cell growth are, therefore, urgently needed. At the same time, the more genetically stable cells of the tumor microenvironment are being recognized as important players in tumor development that can confer resistance to anticancer drugs. Increasing attention is being paid to the tumor microenvironment, including cancer-associated fibroblasts (CAFs). Furthermore, the tumor suppressor gene TP53, which codes for the p53 protein, plays an important role in tumor suppression and cellular stress responses to DNA damage and anti-cancer agents. For this reason, the TP53 gene is frequently mutated in cancer. In the absence of mutations, the p53 protein is often downregulated or inactivated through other mechanisms. This thesis aims to elucidate pathways or mechanisms that contribute to CAF-mediated drug resistance in prostate cancer. The thesis is also focused on investigating a combinatorial therapeutic strategy to improve the effectiveness of the mutant p53-reactivating compound APR-246. The studies in paper I and II revealed that CAFs can enhance cell survival, and affect the sensitivity of prostate cancer cells carrying wild type p53 to chemotherapeutic drugs through different mechanisms. In the paper I, we showed that glutathione, produced by CAFs, protects cancer cells from drug-induced oxidative stress and DNA damage, as it also decreases drug accumulation. In the paper II, we demonstrated that IL-6, one of the soluble factors secreted by CAFs, attenuates the drug-induced p53 response through STAT3 and MDM2. The increased resistance to chemotherapeutic drugs is likely to be a result of the combined effect of glutathione and cytokines like IL-6. In the paper III, we found that inhibition of the efflux pump MRP1 enhances APR-246-induced mutant p53 cancer cell death both in vitro and in vivo. This study also highlighted the impact of the cellular redox status and glutathione content on cancer cell survival and anti-tumor activity of APR-246. In conclusion, pathways or factors that potentially contribute to drug resistance have been the focus of this thesis. Manipulation of these targets in combination with traditional therapies may lead to a more efficient cancer therapy. This thesis also highlights CAFs as a potential target for anti-stromal therapies in prostate cancer.