Ritonavir and ixazomib kill bladder cancer cells by causing ubiquitinated protein accumulation.
There is no curative treatment for advanced bladder cancer. Causing ubiquitinated protein accumulation and endoplasmic reticulum stress is a novel approach to cancer treatment. The HIV protease inhibitor ritonavir has been reported to suppress heat shock protein 90 and increase the amount of unfolded proteins in the cell. If the proteasome functions normally, however, they are rapidly degraded. We postulated that the novel proteasome inhibitor ixazomib combined with ritonavir would kill bladder cancer cells effectively by inhibiting degradation of these unfolded proteins and thereby causing ubiquitinated proteins to accumulate. The combination of ritonavir and ixazomib induced drastic apoptosis and inhibited the growth of bladder cancer cells synergistically. The combination decreased the expression of cyclin D1 and cyclin-dependent kinase 4, and increased the sub-G1fraction significantly. Mechanistically, the combination caused ubiquitinated protein accumulation and endoplasmic reticulum stress. The combination-induced apoptosis was markedly attenuated by the protein synthesis inhibitor cycloheximide, suggesting that the accumulation of ubiquitinated proteins played an important role in the combination's antineoplastic activity. Furthermore, the combination induced histone acetylation cooperatively and the decreased expression of histone deacetylases was thought to be one mechanism of this histone acetylation. The present study provides a theoretical basis for future development of novel ubiquitinated-protein-accumulation-based therapies effective against bladder cancer.
Department of Urology, National Defense Medical College, Tokorozawa, Japan.
Akinori
http://orcid.org/0000-0001-9011-1756
A
Sato
Department of Urology, National Defense Medical College, Tokorozawa, Japan.
Takako
T
Asano
Department of Urology, National Defense Medical College, Tokorozawa, Japan.
Kazuki
K
Okubo
Department of Urology, National Defense Medical College, Tokorozawa, Japan.
Makoto
M
Isono
Department of Urology, National Defense Medical College, Tokorozawa, Japan.
Tomohiko
T
Asano
D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001896:Boron Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D061988:Proteasome Inhibitors / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology*; D057149:Ubiquitinated Proteins / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism*
D000970:Antineoplastic Agents; D001896:Boron Compounds; D061988:Proteasome Inhibitors; D057149:Ubiquitinated Proteins; D019938:Cyclin D1; C548400:ixazomib; D051358:Cyclin-Dependent Kinase 4; D019438:Ritonavir; D005998:Glycine
Bladder cancer; drug combinations; ixazomib; ritonavir; ubiquitinated proteins