Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • 2024-08
  • 2024-09
  • 2024-10

    • br Introduction br Multiple levels of CK AKT

    2021-03-27


    Introduction
    Multiple levels of CK2/AKT cross-talk
    Isoform-specific signaling in CK2/AKT cross-talk Particularly relevant to the scope of this review, it has been shown that depletion of the CK2 catalytic α′ subunit is more effective than that of the α subunit at reducing AKT Ser129 phosphorylation and suppressing AKT downstream signaling (Kreutzer et al., 2010). The issue of AKT isoforms is quite complex. The three AKT isoforms display many overlapping functions. Regardless, isoform-specific substrates have been identified, such as Ankrd2, an AKT2-specific substrate that modulates the balance between proliferation and apoptosis of differentiating myoblasts (Cenni et al., 2011), or lamin A (Cenni et al., 2008, Bertacchini et al., 2013) and palladin (Toker and Marmiroli, 2014, Chin and Toker, 2010) that by Sennoside A are AKT1-specific substrates. Phosphorylation of palladin is especially fascinating, as in this case substrate specificity has been proposed to be driven by the AKT1 linker region (Girardi et al., 2014), namely the region containing the CK2 phosphorylation site (Di Maira et al., 2005). Intriguingly, our studies show that Ser131, the AKT1-Ser129 homolog which lies in the CK2 consensus motif of AKT2, is refractory to phosphorylation by CK2 (Girardi et al., 2014). The differential sensitivity of AKT isoforms to CK2 phosphorylation is therefore directly and causally related to the activity of AKT1, but not AKT2, towards palladin phosphorylation. Since palladin phosphorylation by AKT1 is key to AKT1-mediated inhibition of breast cancer cell migration, one can speculate that CK2 acts as a tuner between pro- or anti-invasion functions of distinct AKT isoforms. Therefore the precise role of both CK2 and AKT in modulating isoform-specific signaling relay may be entirely context-dependent, and requires considerable more work.
    Targeting CK2 and AKT: tools to threaten cancer cell survival? Because of the frequently reported involvement of both CK2 and Akt in cancer, their concomitant targeting could represent a valuable example of ‘multi-kinase therapy’ (Morphy, 2010). Moreover, given the multifaceted cross-talk between CK2 and AKT, targeting of one kinase will affect the other. This is particularly true when blocking CK2, which is frequently upstream of AKT. Several inhibitors of CK2 have already been developed and are under pre-clinical and clinical evaluation. Some of such drugs are cell-permeable, ATP competitive compounds with an in vitro IC50 in the low nanomolar range, narrow specificity towards CK2 (Sarno et al., 2011, Battistutta et al., 2011, Cozza et al., 2013), and trigger apoptosis more successfully in cancer cells compared to normal cells (Cozza et al., 2014), in good agreement with the notion that cancer cells are ‘addicted’ to CK2 (Ruzzene and Pinna, 2010). These compounds have been tested in animal models (reviewed in Venerando et al., 2014) and in clinical trials. As a result, the specific CK2 inhibitor CX-4945 (Siddiqui-Jain et al., 2010) has successfully completed phase I (Pierre et al., 2011, Chon et al., 2015). Besides, the chimeric peptide CIGB-300 (Perea et al., 2008), comprising a Tat-derived cell penetrating peptide and a sequence designed to block the phosphorylation of CK2 substrates, is under clinical investigation for cervical malignancies and is giving encouraging results in term of tolerability and clinical benefit. However it has to be mentioned that the mechanism of action of CIGB-300 is not fully understood (Zanin et al., 2015), and thus this compound cannot be regarded as a bona fide inhibitor of CK2. A growing number of both allosteric and catalytic AKT inhibitors has been developed over the past decade and are under preclinical and clinical evaluation, although most of them display cytostatic, more than cytotoxic, effects (Nitulescu et al., 2016). Importantly, activating mutations of the PI3K/AKT/mTOR pathway can influence the sensitivity to AKT-specific inhibitors to a great extent (Banerji et al., 2012). Moreover, an important limitation in the use of AKT inhibitors in clinical intervention is the emergence of resistance leading to relapse. Recent studies have shown that, in several malignancies, AKT inhibitors used as monotherapy rarely produce durable clinical response primarily due to the onset of mechanisms that lead to compensatory signaling and resistance (Klempner et al., 2013, Bertacchini et al., 2014, Mediani et al., 2016). Therefore, the simultaneous inhibition of several enzymes related to the same pathology, is attracting increasing interest. In this regard, CK2 is a prominent target, not only because it frequently potentiates pro-survival pathways, such as PI3K/AKT, but also because it is directly involved in promoting drug resistance (Di Maira et al., 2007, Di Maira et al., 2008, Zanin et al., 2012, Borgo et al., 2013, Kim et al., 2017).