Chemoresistance and Cancer-Related Inflammation: Two Hallmarks of Cancer Connected by an Atypical Link, PKCζ (original) (raw)
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PKCη is an anti-apoptotic kinase that predicts poor prognosis in breast and lung cancer
Biochemical Society transactions, 2014
The successful treatment of cancer in a disseminated stage using chemotherapy is limited by the occurrence of drug resistance, often mediated by anti-apoptotic mechanisms. Thus the challenge is to pinpoint the underlying key factors and to develop therapies for their direct targeting. Protein kinase C (PKC) enzymes are promising candidates, as some PKCs were shown to be involved in regulation of apoptosis. Our studies and others have shown that PKCη is an anti-apoptotic kinase, able to confer protection on tumour cells against stress and chemotherapy. We have demonstrated that PKCη shuttles between the cytoplasm and the nucleus and that upon DNA damage is tethered at the nuclear membrane. The C1b domain mediates translocation of PKCη to the nuclear envelope and, similar to the full-length protein, could also confer protection against cell death. Furthermore, its localization in cell and nuclear membranes in breast cancer biopsies of neoadjuvant-treated breast cancer patients was an ...
Bentham science
The serine/threonine protein kinase C (PKC) family was first identified as intracellular receptor(s) for the tumor promoting agents phorbol esters. Thirty years after the discovery of PKC, the role of specific PKC isoforms has been described in relationship with an altered pattern of expression in different types of cancer and a good number of small molecule inhibitors (inhibitory peptides, antisense oligonucleotides or natural compounds) targeting PKC are now available. Despite all these achievements and a huge amount of basic research studies on the biochemical regulation of PKC, there has been a delay in clinical trials with drugs targeting PKC function. This delay is easily explained taking into account the extreme biological complexity of the PKC family of isoforms and the incomplete understanding of the specific role of each PKC isozyme in different types of cancers. Some of the difficulties in developing pharmacological compounds selectively tuning the different PKCs have started to be overcome. In this review, the growing evidences of the role of the PKC isoforms , II, , , and is in promoting or counteracting tumor progression will be discussed in relationship with promising therapeutic perspectives.
Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response
Biology
The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially imp...