Overexpression of TNFα induces premature senescence and mitochondrial dysfunctions in melanoma cells in vitro

Overexpression of TNFα induces premature senescence and mitochondrial dysfunctions in melanoma cells in vitro

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ISBN: ISBN 978-80-972360-7-6

Overexpression of TNFα induces premature senescence and mitochondrial dysfunctions in melanoma cells in vitro

Silvia Tyčiaková1 Valéria Valová1,2 Barbora Svitková1 Miroslava Matúšková1
1Ústav experimentálnej onkológie, Biomedicínske centrum SAV, Bratislava, SR
2Katedra genetiky, Prírodovedecká fakulta Univerzity Komenského, Bratislava, SR
silvia.tyciakova@savba.sk

Background: Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with both anti-tumorigenic and pro-tumorigenic activity, affecting tumor cell biology, balance between cell survival and death. Final effect of TNFα is dependent on type of malignant cells, with potential to arrest cancer progression and change the tumor microenvironment to the tumor suppressive conditions.

Methods: In order to investigate diverse changes in cellular and molecular biology upon the TNFα influence in vitro, we engineered malignant melanoma cell line A375 stably expressing this cytokine.

Results: Under the TNFα overexpression, significant upregulation of proinflammatory cytokine IL6 gene was observed. Melanoma cells A375/hTNFα displayed increased autophagy on day 3, followed by premature senescence on day 6. Both processes seem to be interconnected, following earlier apoptosis induction and deregulation of mitochondrial functions. We documented altered mitochondrial status, lowered ATP production, lowered mitochondrial mass, and changes in mitochondrial morphology. Overexpression of TNFα was not linked with significant affection of the subpopulation of cancer stem-like cells (CSCs) in vitro. However, we could demonstrate a decrease by up to 50% of aldehyde dehydrogenase (ALDH) activity, which is linked to the stemness phenotype.

Conclusions: Our in vitro study of direct TNFα influence provides complex report of cellular processes initiated in malignant melanoma cells. Despite high overexpression of TNFα protein in engineered tumor cells, the subpopulation of CSCs responsible for tumor growth initiation remained unaffected, and probably is not directly linked with the loss of tumorigenic potential.

Poďakovanie: 

Acknowledgement: This work was supported by grants VEGA 02/0050/19, VEGA 02/0185/21, Ministry of Health of the Slovak Republic under the project registration number 2019/60-BMCSAV-4, EU Horizon 2020 Research and Innovation programme under grant agreement No 857381 (VISION) and Slovak Cancer Research Foundation RFL2009 and RFL2012 programs.

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Diskusia

Melanómy sú agresívne nádory a ich liečba, hlavne v neskoršom štádiu a pri metastatickom melanome, je veľmi obmedzená. Preto je výborne zamerať sa na ne a použiť overexpresiu TNFa na indukciu autofagie a senescencie. Bolo by potrebných viac projektov, ktoré by skúmali zmenu mikroprostredia nádoru tak, aby nepodporoval jeho rast.

Dakujem za komentar. Keby sme vedeli mikroprostredie nadoru urobit viac "tumor-supresivnym", napr. aj pomocou cytokinov, alebo stimulaciou protinadorovej imunitnej odpovede, znamenalo by to nadej, ako dosiahnut spomalenie rastu nadorovej masy.

Dobry den, mate velmi pekne spracovany a bohaty prispevok. :) Ako by sa dali vami ziskane poznatky vyuzit v terapii metastatickych melanomov? Planujete sa pozriet napriklad na to, ci by overexpresia TNFa nemohla zvysit ucinnost standardnej cytostatickej liecby? Mne sa nahodou paci, ze ste pozorovali iba mierny vplyv samotneho TNFa na analyzovane parametre, avsak v kombinacii s inymi latkami by mohol nastat vyrazny synergicky efekt, ale mozno s mensimi neziaducimi ucinkami.

Dakujem velmi pekne za komentar. V nasej praci sme sa zamerali na pleiotroplny ucinok TNFalfa na bunkovu biologiu melanomu in vitro. TNFalfa je vsak ovela ucinnejsi in vivo, pretoze posobi aj na nenadorove bunky stromy nadoru, napr. na endotelove bunky. Od klinickeho pouzitia, systemoveho podania TNFalfa, sa vsak uz davnejsie ustupilo, pretoze navodzuje systemovu toxicitu. Uspesne sa vsak da pouzit pri lokalnom podavani a v kombinacii s chemoterapeutikami je mozne dosiahnut dobry synergicky efekt pri liecbe sarkomov a melanomov (metoda "isolated limb perfusion"). Viacero timov sa dnes zaobera zacielenim TNFalfa do miesta nadoru a dufajme, ze sa podari tento cytokin neskor vyuzit v protinadorovej terapii, v ovplyvneni mikroprostredia nadoru. Treba byt vsak opatrny, TNFalfa moze mat aj pro-nadorovy ucinok.