Research output: Contribution to journal › Article › peer-review
Cytotoxic and antitumor activity of lactaptin in combination with autophagy inducers and inhibitors. / Bagamanshina, Anastasia V.; Troitskaya, Olga S.; Nushtaeva, Anna A. et al.
In: BioMed Research International, Vol. 2019, 4087160, 17.06.2019, p. 4087160.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Cytotoxic and antitumor activity of lactaptin in combination with autophagy inducers and inhibitors
AU - Bagamanshina, Anastasia V.
AU - Troitskaya, Olga S.
AU - Nushtaeva, Anna A.
AU - Yunusova, Anastasia Yu
AU - Starykovych, Marina O.
AU - Kuligina, Elena V.
AU - Kit, Yuri Ya
AU - Richter, Max
AU - Wohlfromm, Fabian
AU - Kähne, Thilo
AU - Lavrik, Inna N.
AU - Richter, Vladimir A.
AU - Koval, Olga A.
PY - 2019/6/17
Y1 - 2019/6/17
N2 - Autophagy is a degradative process in which cellular organelles and proteins are recycled to restore homeostasis and cellular metabolism. Autophagy can be either a prosurvival or a prodeath process and remains one of the most fundamental processes for cell vitality. Thus autophagy modulation is an important approach for reinforcement anticancer therapeutics. Earlier we have demonstrated that recombinant analog of human milk protein lactaptin (RL2) induced apoptosis of various cultured cancer cells and activated lipidation of microtubule-associated protein 1 light chain 3 (LC3). In this study we investigated whether autophagy inhibitors-chloroquine (CQ), Ku55933 (Ku), and 3-methyladenine (3MA)-or inducer-rapamycin (Rap)-can enhance cytotoxic activity of lactaptin analog in cancer cells and its anticancer activity in the mice model. Western Blot analysis revealed that RL2 induced short-term autophagy in MDA-MB-231 and MCF-7 cells at early stages of incubation and that these data were confirmed by the transmission electron microscopy of autophagosome/autophagolysosome formation. RL2 stimulates reactive oxygen species (ROS) production, autophagosomes accumulation, upregulation of ATG5 with processing of LC3I to LC3II, and downregulation of p62/sequestosome 1 (p62). We have shown that autophagy modulators, CQ, Ku, and Rap, synergistically increased cytotoxicity of RL2, and RL2 with CQ induced autophagic cell death. In addition, CQ, Ku, and Rap in combination with RL2 decreased activity of lysosomal protease Cathepsin D. More importantly, combining RL2 with CQ, we improved antitumor effect in mice. Detected synergistic cytotoxic effects of both types of autophagy regulators, inhibitors, and inducers with RL2 against cancer cells allow us to believe that these combinations can be a basis for the new anticancer approach. Finally, we suppose that CQ and Rap promoting of short-term RL2-induced autophagy interlinks with final autophagic cell death.
AB - Autophagy is a degradative process in which cellular organelles and proteins are recycled to restore homeostasis and cellular metabolism. Autophagy can be either a prosurvival or a prodeath process and remains one of the most fundamental processes for cell vitality. Thus autophagy modulation is an important approach for reinforcement anticancer therapeutics. Earlier we have demonstrated that recombinant analog of human milk protein lactaptin (RL2) induced apoptosis of various cultured cancer cells and activated lipidation of microtubule-associated protein 1 light chain 3 (LC3). In this study we investigated whether autophagy inhibitors-chloroquine (CQ), Ku55933 (Ku), and 3-methyladenine (3MA)-or inducer-rapamycin (Rap)-can enhance cytotoxic activity of lactaptin analog in cancer cells and its anticancer activity in the mice model. Western Blot analysis revealed that RL2 induced short-term autophagy in MDA-MB-231 and MCF-7 cells at early stages of incubation and that these data were confirmed by the transmission electron microscopy of autophagosome/autophagolysosome formation. RL2 stimulates reactive oxygen species (ROS) production, autophagosomes accumulation, upregulation of ATG5 with processing of LC3I to LC3II, and downregulation of p62/sequestosome 1 (p62). We have shown that autophagy modulators, CQ, Ku, and Rap, synergistically increased cytotoxicity of RL2, and RL2 with CQ induced autophagic cell death. In addition, CQ, Ku, and Rap in combination with RL2 decreased activity of lysosomal protease Cathepsin D. More importantly, combining RL2 with CQ, we improved antitumor effect in mice. Detected synergistic cytotoxic effects of both types of autophagy regulators, inhibitors, and inducers with RL2 against cancer cells allow us to believe that these combinations can be a basis for the new anticancer approach. Finally, we suppose that CQ and Rap promoting of short-term RL2-induced autophagy interlinks with final autophagic cell death.
KW - CELL-DEATH
KW - ACTIVATION
KW - SPERMIDINE
KW - APOPTOSIS
KW - RESPONSES
KW - PATHWAYS
KW - CANCER
UR - http://www.scopus.com/inward/record.url?scp=85068584748&partnerID=8YFLogxK
U2 - 10.1155/2019/4087160
DO - 10.1155/2019/4087160
M3 - Article
C2 - 31317028
AN - SCOPUS:85068584748
VL - 2019
SP - 4087160
JO - BioMed Research International
JF - BioMed Research International
SN - 2314-6133
M1 - 4087160
ER -
ID: 20779049