title: The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells.
abstract: The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer.
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Lymor
authors.initials: L
authors.lastname: Ringer
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Sirajuddin
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Tricoli
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Waye
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Muhammad Umer
authors.initials: MU
authors.lastname: Choudhry
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Parasido
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Angiela
authors.initials: A
authors.lastname: Sivakumar
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Heckler
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Aisha
authors.initials: A
authors.lastname: Naeem
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. National Cancer Institute of Egypt, Cairo, Egypt.
authors.forename: Iman
authors.initials: I
authors.lastname: Abdelgawad
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Massachusetts General Hospital, Boston, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Feldman
authors.affiliation: Massachusetts General Hospital, Boston, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Massachusetts General Hospital, Boston, USA.
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Yenugonda
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.affiliation: Georgetown University Hospital, Washington, DC, USA.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Dritschilo
authors.affiliation: Georgetown University Hospital, Washington, DC, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lynch
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Schlegel
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Rodriguez
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Avantaggiati
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation; D003619:Dansyl Compounds / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C557984:2-chloro-N-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)-4-(2-(1-hydroxy-3-methylbutan-2-ylamino)-9-isopropyl-9H-purin-6-ylamino)benzamide; D003619:Dansyl Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000225:Adenine