Abstract
Protein kinase CK2 is a highly conserved and constitutively active Ser/Thr-kinase that phosphorylates a large number of substrates, resulting in increased cell proliferation and survival. A known target of CK2 is Akt, a player in the PI3K/Akt/mTORC1 signaling pathway, which is aberrantly activated in 32% of colorectal cancer (CRC) patients. On the other hand, mTORC1 plays an important role in the regulation of protein synthesis, cell growth, and autophagy. Some studies suggest that CK2 regulates mTORC1 in several cancers. The most recently developed CK2 inhibitor, silmitasertib (formerly CX-4945), has been tested in phase I/II trials for cholangiocarcinoma and multiple myeloma. This drug has been shown to induce autophagy and enhance apoptosis in pancreatic cancer cells and to promote apoptosis in non-small cell lung cancer cells. Nevertheless, it has not been tested in studies for CRC patients. We show in this work that inhibition of CK2 with silmitasertib decreases in vitro tumorigenesis of CRC cells in response to G2/M arrest, which correlates with mTORC1 inhibition and formation of large cytoplasmic vacuoles. Notably, molecular markers indicate that these vacuoles derive from massive macropinocytosis. Altogether, these findings suggest that an aberrantly elevated expression/activity of CK2 may play a key role in CRC, promoting cell viability and proliferation in untreated cells, however, its inhibition with silmitasertib promotes methuosis-like cell death associated to massive catastrophic vacuolization, accounting for decreased tumorigenicity at later times. These characteristics of silmitasertib support a potential therapeutic use in CRC patients and probably other CK2-dependent cancers.
Highlights
Colorectal cancer (CRC) is a multifactorial disease affecting millions of people worldwide and has been linked to deregulation of several signaling pathways
A key downstream component of the PI3K/Akt signaling pathway is the mammalian target of rapamycin complex 1, which plays an important role in different types of cancer, including CRC4,5
Decreased viability of CRC cells correlated with diminished proliferation (Fig. 2b) and late apoptosis, as observed by PARP-1 cleavage and annexin-V+/propidium iodide (PI)+ staining after 48 h (Fig. 2c, d), the pan-caspase inhibitor Z-VAD-FMK was unable to revert the decreased viability both at 24 h and 48 h (Supp Fig. 1A)
Summary
Colorectal cancer (CRC) is a multifactorial disease affecting millions of people worldwide and has been linked to deregulation of several signaling pathways. The PI3K/Akt signaling pathway plays an important role in a variety of cancers due to its association with processes that promote proliferation, resistance to apoptosis,. A key downstream component of the PI3K/Akt signaling pathway is the mammalian target of rapamycin complex 1 (mTORC1), which plays an important role in different types of cancer, including CRC4,5. The core component of this complex, the mammalian target of Official journal of the Cell Death Differentiation Association. Silva-Pavez et al Cell Death and Disease (2019)10:73 rapamycin (mTOR), is a highly conserved Ser/Thr-kinase that integrates growth factor and nutritional signals to promote growth and survival of normal cells. MTORC1 plays an important role in the regulation of protein synthesis, cell growth and autophagy in response to nutrients and growth factors[8]. Treatment with rapamycin leads to a reduction of tumors in an in vivo model of PI3K-dependent CRC11
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