A subpopulation of tumor cells with distinct stem-like properties (cancer stem-like cells, CSCs) may be responsible for tumor initiation, invasive growth, and possibly dissemination to distant organ sites. CSCs exhibit a spectrum of biological, biochemical, and molecular features that are consistent with a stem-like phenotype, including growth as non-adherent spheres (clonogenic potential), ability to form a new tumor in xenograft assays, unlimited self-renewal, and the capacity for multipotency and lineage-specific differentiation.
PKCdelta is a novel class serine/threonine kinase of the PKC family, and functions in a number of cellular activities including cell proliferation, survival or apoptosis. PKCdelta has previously been validated as a synthetic lethal target in cancer cells of multiple types with aberrant activation of Ras signaling, using both genetic (shRNA and dominant-negative PKCdelta mutants) and small molecule inhibitors.
In contrast, PKCdelta is not required for the proliferation or survival of normal cells, suggesting the potential tumor-specificity of a PKCdelta-targeted approach.
Methods:
shRNA knockdown was used validate PKCdelta[unknown] as a target in primary cancer stem cell lines, and stem-like cells derived from human tumor cell lines, including breast, pancreatic, prostate and melanoma tumor cells. Novel and potent small molecule PKCdelta inhibitors were employed in assays monitoring apoptosis, proliferation and clonogenic capacity of these cancer stem-like populations.
Significant differences among data sets were determined using two-tailed Student’s t tests or ANOVA.
Results:
We demonstrate that CSC-like populations derived from multiple types of human primary tumors, from human cancer cell lines, and from transformed human cells, require PKCdelta activity and are susceptible to agents which deplete PKCdelta protein or activity. Inhibition of PKCdelta by specific genetic strategies (shRNA) or by novel small molecule inhibitors is growth inhibitory and cytotoxic to multiple types of human CSCs in culture.
PKCdelta inhibition efficiently prevents tumor sphere outgrowth from tumor cell cultures, with exposure times as short as six hours. Small-molecule PKCdelta inhibitors also inhibit human CSC growth in vivo in a mouse xenograft model.
Conclusions:
These findings suggest that the novel PKC isozyme PKCdelta may represent a new molecular target for cancer stem cell populations.
Author: Zhihong ChenLora W FormanRobert M WilliamsDouglas V Faller
Credits/Source: BMC Cancer 2014, 14:90
Published on: 2014-02-14
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