Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response

Angelika Szokalska, Marcin Makowski, Dominika Nowis, Grzegorz M. Wilczyński, Marek Kujawa, Cezary Wojcik, Izabela Młynarczuk-Biały, Pawel Salwa, Jacek Bil, Sylwia Janowska, Patrizia Agostinis, Tom Verfaillie, Marek Bugajski, Jan Gietka, Tadeusz Issat, Eliza Głodkowska, Piotr Mrówka, Tomasz Stoklosa, Michael R. Hamblin, Paweł Mróz & 2 others Marek Jakóbisiak, Jakub Golab

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors.

Original languageEnglish (US)
Pages (from-to)4235-4243
Number of pages9
JournalCancer Research
Volume69
Issue number10
DOIs
StatePublished - May 15 2009
Externally publishedYes

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Unfolded Protein Response
Endoplasmic Reticulum Stress
Photochemotherapy
Proteasome Endopeptidase Complex
Heat-Shock Proteins
Proteasome Inhibitors
Neoplasms
Protein Unfolding
Dihematoporphyrin Ether
Ubiquitinated Proteins
Singlet Oxygen
Proteins
Endoplasmic Reticulum
Reactive Oxygen Species
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response. / Szokalska, Angelika; Makowski, Marcin; Nowis, Dominika; Wilczyński, Grzegorz M.; Kujawa, Marek; Wojcik, Cezary; Młynarczuk-Biały, Izabela; Salwa, Pawel; Bil, Jacek; Janowska, Sylwia; Agostinis, Patrizia; Verfaillie, Tom; Bugajski, Marek; Gietka, Jan; Issat, Tadeusz; Głodkowska, Eliza; Mrówka, Piotr; Stoklosa, Tomasz; Hamblin, Michael R.; Mróz, Paweł; Jakóbisiak, Marek; Golab, Jakub.

In: Cancer Research, Vol. 69, No. 10, 15.05.2009, p. 4235-4243.

Research output: Contribution to journalArticle

Szokalska, A, Makowski, M, Nowis, D, Wilczyński, GM, Kujawa, M, Wojcik, C, Młynarczuk-Biały, I, Salwa, P, Bil, J, Janowska, S, Agostinis, P, Verfaillie, T, Bugajski, M, Gietka, J, Issat, T, Głodkowska, E, Mrówka, P, Stoklosa, T, Hamblin, MR, Mróz, P, Jakóbisiak, M & Golab, J 2009, 'Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response', Cancer Research, vol. 69, no. 10, pp. 4235-4243. https://doi.org/10.1158/0008-5472.CAN-08-3439
Szokalska, Angelika ; Makowski, Marcin ; Nowis, Dominika ; Wilczyński, Grzegorz M. ; Kujawa, Marek ; Wojcik, Cezary ; Młynarczuk-Biały, Izabela ; Salwa, Pawel ; Bil, Jacek ; Janowska, Sylwia ; Agostinis, Patrizia ; Verfaillie, Tom ; Bugajski, Marek ; Gietka, Jan ; Issat, Tadeusz ; Głodkowska, Eliza ; Mrówka, Piotr ; Stoklosa, Tomasz ; Hamblin, Michael R. ; Mróz, Paweł ; Jakóbisiak, Marek ; Golab, Jakub. / Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response. In: Cancer Research. 2009 ; Vol. 69, No. 10. pp. 4235-4243.
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abstract = "Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60{\%} to 100{\%} complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors.",
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AU - Szokalska, Angelika

AU - Makowski, Marcin

AU - Nowis, Dominika

AU - Wilczyński, Grzegorz M.

AU - Kujawa, Marek

AU - Wojcik, Cezary

AU - Młynarczuk-Biały, Izabela

AU - Salwa, Pawel

AU - Bil, Jacek

AU - Janowska, Sylwia

AU - Agostinis, Patrizia

AU - Verfaillie, Tom

AU - Bugajski, Marek

AU - Gietka, Jan

AU - Issat, Tadeusz

AU - Głodkowska, Eliza

AU - Mrówka, Piotr

AU - Stoklosa, Tomasz

AU - Hamblin, Michael R.

AU - Mróz, Paweł

AU - Jakóbisiak, Marek

AU - Golab, Jakub

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