p53 and cancer-associated fibroblasts : implications for cancer therapy and drug resistance
Author: Chete, Emarndeena H
Date: 2020-10-26
Location: BioClinicum, J3:14 Kerstin Hagenfeldt, Karolinska University Hospital, Solna
Time: 09.00
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
View/ Open:
Thesis (13.54Mb)
Abstract
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.
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.
List of papers:
I. Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death. Emarndeena H. Cheteh, Martin Augsten, Helene Rundqvist, Julie Bianchi, Victoria Sarne, Lars Egevad, Vladimir JV Bykov, Arne Östman, Klas G Wiman. Cell Death Dis. 2017 Jun 1;8(6):e2848.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. 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. Cell Death Discov. 2020 Jun 2;6:42.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death. Sophia Ceder, Sofi E. Eriksson, Emarndeena H. Cheteh, Swati Dawar, Mariana Corrales Benitez, Vladimir Bykov, Kenji M. Fujihara, Lars Abrahmsen, Nicholas J. Clemons, Klas G. Wiman. [Accepted]
Fulltext (DOI)
Pubmed
I. Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death. Emarndeena H. Cheteh, Martin Augsten, Helene Rundqvist, Julie Bianchi, Victoria Sarne, Lars Egevad, Vladimir JV Bykov, Arne Östman, Klas G Wiman. Cell Death Dis. 2017 Jun 1;8(6):e2848.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. 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. Cell Death Discov. 2020 Jun 2;6:42.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death. Sophia Ceder, Sofi E. Eriksson, Emarndeena H. Cheteh, Swati Dawar, Mariana Corrales Benitez, Vladimir Bykov, Kenji M. Fujihara, Lars Abrahmsen, Nicholas J. Clemons, Klas G. Wiman. [Accepted]
Fulltext (DOI)
Pubmed
Institution: Karolinska Institutet
Supervisor: Wiman, Klas G
Co-supervisor: Östman, Arne
Issue date: 2020-10-01
Rights:
Publication year: 2020
ISBN: 978-91-7831-983-1
Statistics
Total Visits
Views | |
---|---|
p53 ... | 688 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
p53 ... | 24 | 15 | 17 | 24 | 24 | 31 | 17 |
File Visits
Views | |
---|---|
Thesis_Emarndeena_H. Cheteh.pdf | 284 |
Emarndeena doctoral thesis.pdf | 1 |
Top country views
Views | |
---|---|
Sweden | 125 |
United States | 101 |
Ireland | 97 |
United Kingdom | 64 |
Australia | 63 |
Germany | 56 |
China | 37 |
South Korea | 14 |
Finland | 11 |
France | 8 |
Top cities views
Views | |
---|---|
Dublin | 97 |
Sydney | 56 |
Ashburn | 20 |
Stockholm | 20 |
Hangzhou | 19 |
Huddinge | 19 |
Sundbyberg | 7 |
Bromma | 6 |
Gdańsk | 6 |
Helsinki | 6 |