Combination therapy induces unfolded protein response and cytoskeletal rearrangement leading to mitochondrial apoptosis in prostate cancer.
Development of therapeutic resistance is responsible for most prostate cancer (PCa) related mortality. Resistance has been attributed to an acquired or selected cancer stem cell phenotype. Here we report the histone deacetylase inhibitor apicidin (APC) or ER stressor thapsigargin (TG) potentiate paclitaxel (TXL)-induced apoptosis in PCa cells and limit accumulation of cancer stem cells. TXL-induced responses were modulated in the presence of TG with increased accumulation of cells at G1-phase, rearrangement of the cytoskeleton, and changes in cytokine release. Cytoskeletal rearrangement was associated with modulation of the cytoplasmic and mitochondrial unfolded protein response leading to mitochondrial dysfunction and release of proapoptotic proteins from mitochondria. TXL in combination with APC or TG enhanced caspase activation. Importantly, TXL in combination with TG induced caspase activation and apoptosis in X-ray resistant LNCaP cells. Increased release of transforming growth factor-beta (TGF-β) was observed while phosphorylated β-catenin level was suppressed with TXL combination treatments. This was accompanied by a decrease in the CD44(+)CD133(+) cancer stem cell-like population, suggesting treatment affects cancer stem cell properties. Taken together, combination treatment with TXL and either APC or TG induces efficient apoptosis in both proliferating and cancer stem cells, suggesting this therapeutic combination may overcome drug resistance and recurrence in PCa.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Sandeep
S
Kumar
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Ajay K
AK
Chaudhary
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Rahul
R
Kumar
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Jordan
J
O'Malley
OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstrasse, Dresden, Germany; German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Anna
A
Dubrovska
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Xinjiang
X
Wang
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Neelu
N
Yadav
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
David W
DW
Goodrich
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Electronic address: dhyan.chandra@roswellpark.org.
Dhyan
D
Chandra
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D017239:Paclitaxel; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D017382:Reactive Oxygen Species / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects / Q000528:radiation effects; D014965:X-Rays; D051176:beta Catenin / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D016209:Interleukin-8; D010456:Peptides, Cyclic; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; C102351:apicidin; D051176:beta Catenin; D019284:Thapsigargin; D007371:Interferon-gamma; D020169:Caspases; D020782:Matrix Metalloproteinases; D017239:Paclitaxel
Anticancer drugs; Apoptosis; Combination therapy; Mitochondria; Prostate cancer; Unfolded protein response