Browsing by Author "Citrin, Deborah E."

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    Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation
    (American Association for Cancer Research, 2022) Owens, Jake L.; Beketova, Elena; Liu, Sheng; Shen, Qi; Pawar, Jogendra Singh; Asberry, Andrew M.; Yang, Jie; Deng, Xuehong; Elzey, Bennett D.; Ratliff, Timothy L.; Cheng, Liang; Choo, Richard; Citrin, Deborah E.; Polascik, Thomas J.; Wang, Bangchen; Huang, Jiaoti; Li, Chenglong; Wan, Jun; Hu, Chang-Deng; Medical and Molecular Genetics, School of Medicine
    Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.
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    Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
    (Oxford, 2021-10) Prasanna, Pataje G.; Citrin, Deborah E.; Hildesheim, Jeffrey; Ahmed, Mansoor M.; Venkatachalam, Sundar; Riscuta, Gabriela; Xi, Dan; Zheng, Guangrong; van Deursen, Jan; Goronzy, Jorg; Kron, Stephen J.; Anscher, Mitchell S.; Sharpless, Norman E.; Campisi, Judith; Brown, Stephen L.; Niedernhofer, Laura J.; O’Loghlen, Ana; Georgakilas, Alexandros G.; Paris, Francois; Gius, David; Gewirtz, David A.; Schmitt, Clemens A.; Abazeed, Mohamed E.; Kirkland, James L.; Richmond, Ann; Romesser, Paul B.; Lowe, Scott W.; Gil, Jesus; Mendonca, Marc S.; Burma, Sandeep; Zhou, Daohong; Coleman, C. Norman; Radiation Oncology, School of Medicine
    Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.