Regulation of TP53INP2 protein by kinases

Radivojevikj, Dragana (avtor), Petrovič, Uroš (mentor), Ivanova, Saška (komentor)

Cancer was the leading cause of death in 2020 worldwide, consequently it exerts a huge burden on the health care system and on people’s lives. An early detection and correct treatment are crucial for curing cancer. Biomarkers are an effective tool used by clinicians to predict who will benefit from a certain treatment. One such potential biomarker is the protein TP53INP2, more specifically for the anticancer treatment TRAIL. TP53INP2 is an intrinsically disordered protein with many different roles in the cell. Protein levels of TP53INP2 are increased when kinases such as Checkpoint 1 kinase (Chk1), Casein kinase 2 (CK2), and Cyclin-dependent kinases 4 or 6 (CDK4,6) are inhibited. In this thesis it is shown that in the Ishikawa, SH-SY5Y and MDA-MB-231 cell lines TP53INP2 levels increase when treated with inhibitors Palbociclib (CDK4,6 inhibitor), Silmitasertib (CK2 inhibitor), or Chk1 inhibitor. Moreover, this increase in protein abundance is not due to an increase in gene expression, therefore phosphorylation probably marks TP53INP2 for degradation. TP53INP2 sensitizes cancer cells to synergistic treatment with TRAIL and kinase inhibitors of CDK4,6, CK2, and Chk1. The Ishikawa cells die more often by apoptosis when treated with the combined treatment (TRAIL and kinase inhibition) than when treated with TRAIL alone. However, the loss of TP53INP2 abrogated apoptosis, suggesting that the levels of TP53INP2 could be used as a biomarker for this combined treatment. Our results indicate that TP53INP2 is a potential biomarker for combination anticancer treatment with TRAIL and the above mentioned kinase inhibitors. Further research is needed to better understand the full importance of this protein in the fight against cancer.

• Jezik: Angleški jezik
• Ključne besede: Cancer, Biomarker, Apoptosis, Cancer treatment, Kinases
• Vrsta gradiva: Magistrsko delo/naloga
• Tipologija: 2.09 - Magistrsko delo
• Organizacija: BF - Biotehniška fakulteta
• Kraj izida: Ljubljana
• Založnik: [D. Radivojevikj]
• Leto izida: 2022
• PID: 20.500.12556/RUL-138790
• UDK: 576
• COBISS.SI-ID: 120273155
• Datum objave v RUL: 18.08.2022

Sekundarni jezik

• Jezik: Slovenski jezik
• Naslov: Regulacija proteina TP53INP2 s kinazami

Izvleček

Rak je bil v letu 2020 najpogostejši vzrok smrti na svetu in tako predstavlja veliko breme za zdravstveni sistem in življenja ljudi. Zgodnje odkrivanje in pravilno zdravljenje sta ključna za ozdravitev teh bolezni. Biomarkerji so učinkovito orodje, ki ga zdravniki uporabljajo za napovedovanje, komu bo določeno zdravljenje koristilo. Eden od takšnih primerov je protein TP53INP2, ki je potencialni biomarker zlasti za protirakavo zdravilo TRAIL. TP53INP2 je intrinzično neurejen protein s številnimi različnimi vlogami v celici. Raven proteina TP53INP2 se poveča, kadar so kinaze, kot so kinaza Chk 1, kazein kinaza 2 (CK2) ter od ciklina odvisni kinazi 4 in 6 (CDK4,6), inhibirane. V tem magistrskem delu smo ugotovili, da se v celicah celičnh linij Ishikawa, SH-SY5Y in MDA-MB-231 raven proteina TP53INP2 poveča, če jih izpostavimo inhibitorjem Palbociclib (zaviralec CDK4,6), Silmitasertib (zaviralec CK2) oziroma inhibitorjem Chk1. Poleg tega to povečanje koncentracije proteina ni posledica povečanja izražanja gena, tako da fosforilacija verjetno označi TP53INP2, da se ta razgradi. TP53INP2 senzibilizira rakave celice tako, da te postanejo bolj občutljive za kombinirano sinergistično zdravljenje s TRAIL in inhibitorji kinaz CDK4,6, CK2 in Chk1. Celice Ishikawa v večji meri umirajo z apoptozo, če jih zdravimo s kombiniranim zdravljenjem (TRAIL in inhibitorji kinaz), kakor če jih zdravimo samo s TRAIL. Izguba TP53INP2 pa je odpravila apoptozo, kar nakazuje, da bi lahko raven proteina TP53INP2 uporabili kot biomarker za to kombinirano zdravljenje. Naši rezultati kažejo, da je TP53INP2 potencialni biomarker za kombinirano protirakavo zdravljenje s TRAIL in prej omenjenimi zaviralci kinaz.

• Ključne besede: Rak, Biomarkerji, Apoptoza, Protirakovno zdravilo, Kinazi