HIV-1 Reverse Transcriptase Promotes Tumor Growth and Metastasis Formation via ROS-Dependent Upregulation of Twist

Bayurova, E.; Jansons, J.; Skrastina, D.; Smirnova, O.; Mezale, D.; Kostyusheva, A.; Kostyushev, D.; Petkov, S.; Podschwadt, P.; Valuev-Elliston, V.; Sasinovich, S.; Korolev, S.; Warholm, P.; Latanova, A.; Starodubova, E.; Tukhvatulin, A.; Latyshev, O.; Selimov, R.; Metalnikov, P.; Komarov, A.; Ivanova, O.; Gorodnicheva, T.; Kochetkov, S.; Gottikh, M.; Strumfa, I.; Ivanov, A.; Gordeychuk, I.; Isaguliants, M.

Авторы: Ekaterina Bayurova, Juris Jansons, Dace Skrastina, Olga Smirnova, Dzeina Mezale, Anastasia Kostyusheva, Dmitry Kostyushev, Stefan Petkov, Philip Podschwadt, Vladimir Valuev-Elliston, Sviataslau Sasinovich, Sergey Korolev, Per Warholm, Anastasia Latanova, Elizaveta Starodubova, Amir Tukhvatulin, Oleg Latyshev, Renat Selimov, Pavel Metalnikov, Alexander Komarov, Olga Ivanova, Tatiana Gorodnicheva, Sergey Kochetkov, Marina Gottikh, Ilze Strumfa, Alexander Ivanov, Ilya Gordeychuk, Maria Isaguliants
Журнал: Oxidative Medicine and Cellular Longevity
Том: 2019
Год издания: 2019
Издательство: Landes Bioscience
Местоположение издательства: United States
Первая страница: 1
Последняя страница: 29
DOI: 10.1155/2019/6016278
Аннотация: HIV-induced immune suppression results in the high prevalence of HIV/AIDS-associated malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer. HIV-infected people are also at an increased risk of “non-AIDS-defining” malignancies not directly linked to immune suppression but associated with viral infections. Their incidence is increasing despite successful antiretroviral therapy. The mechanism behind this phenomenon remains unclear. Here, we obtained daughter clones of murine mammary gland adenocarcinoma 4T1luc2 cells expressing consensus reverse transcriptase of HIV-1 subtype A FSU_A strain (RT_A) with and without primary mutations of drug resistance. In in vitro tests, mutations of resistance to nucleoside inhibitors K65R/M184V reduced the polymerase, and to nonnucleoside inhibitors K103N/G190S, the RNase H activities of RT_A. Expression of these RT_A variants in 4T1luc2 cells led to increased production of the reactive oxygen species (ROS), lipid peroxidation, enhanced cell motility in the wound healing assay, and upregulation of expression of Vimentin and Twist. These properties, particularly, the expression of Twist, correlated with the levels of expression RT_A and/or the production of ROS. When implanted into syngeneic BALB/C mice, 4T1luc2 cells expressing nonmutated RT_A demonstrated enhanced rate of tumor growth and increased metastatic activity, dependent on the level of expression of RT_A and Twist. No enhancement was observed for the clones expressing mutated RT_A variants. Plausible mechanisms are discussed involving differential interactions of mutated and nonmutated RTs with its cellular partners involved in the regulation of ROS. This study establishes links between the expression of HIV-1 RT, production of ROS, induction of EMT, and enhanced propagation of RTexpressing tumor cells. Such scenario can be proposed as one of the mechanisms of HIV-induced/enhanced carcinogenesis not associated with immune suppression.
Добавил в систему: Королев Сергей Павлович

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