Senescence is characterized by permanent cell-cycle arrest despite continued viability and metabolic activity, in conjunction with the secretion of a complex mixture of extracellular proteins and soluble factors known as the senescence-associated secretory phenotype (SASP). Cellular senescence has been shown to prevent the proliferation of potentially tumorigenic cells, and is thus generally considered a tumor suppressive process. However, some SASP components may act as pro-tumorigenic mediators on premalignant cells in the microenvironment. A limited number of studies indicated that protein kinase C (PKC) has a role in senescence, with different isoforms having opposing effects. It is therefore important to elucidate the functional role of specific PKCs in senescence. Here we show that PKCη, an epithelial specific and anti-apoptotic kinase, promotes senescence induced by oxidative stress and DNA damage. We further demonstrate that PKCη promotes senescence through its ability to upregulate the expression of the cell cycle inhibitors p21Cip1 and p27Kip1 and enhance transcription and secretion of interleukin-6 (IL-6). Moreover, we demonstrate that PKCη creates a positive loop for reinforcing senescence by increasing the transcription of both IL-6 and IL-6 receptor, whereas the expression of IL-8 is specifically suppressed by PKCη. Thus, the presence/absence of PKCη modulates major components of SASP. Furthermore, we show that the human polymorphic variant of PKCη, 374I, that exhibits higher kinase activity in comparison to WT-374V, is also more effective in IL-6 secretion, p21Cip1 expression and the promotion of senescence, further supporting a role for PKCη in senescence. As there is now considerable interest in senescence activation/elimination to control tumor progression, it is first crucial to reveal the molecular regulators of senescence. This will improve our ability to develop new strategies to harness senescence as a potential cancer therapy in the future.

Hodgkin's Lymphoma (HL) is one of the most prevailing malignancies in young adults. Reed–Sternberg (RS) cells in HL have distinctive large cell morphology, are characteristic of the disease and their presence is essential for diagnosis. Enlarged cells are one of the hallmarks of senescence, but whether RS cells are senescent has not been previously investigated. Here we show that RS cells have characteristics of senescent cells; RS cells in HL biopsies specifically express the senescence markers and cell cycle inhibitors p21Cip1 and p16INK4a and are negative for the proliferation marker Ki-67, suggesting that these cells have ceased to proliferate. Moreover, the RS-like cells in HL lines, stained specifically for senescence-associated β-galactosidase (SA-β-gal). Oxidative stress promoted senescence in these cells as demonstrated by their staining for p21Cip1, p16INK4a, p53 and γH2AX. Senescent cells produce copious amounts of inflammatory cytokines termed ‘senescence-associated secretory phenotype' (SASP), primarily regulated by Nuclear Factor κB (NF-κB). Indeed, we show that NF-κB activity and NF-κB-dependent cytokines production (e.g., IL-6, TNF-α, GM-CSF) were elevated in RS-like cells. Furthermore, NF-κB inhibitors, JSH-23 and curcumin reduced IL-6 secretion from RS-like cells. Thus, defining RS cells as senescent offers new insights on the origin of the proinflammatory microenvironment in HL.

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Polyploidy-or chromosome doubling-plays a significant role in plant speciation and evolution. Much of the existing evidence indicates that fusion of unreduced (or 2n) gametes is the major pathway responsible for polyploid formation. In the early 1900s, a theory was put forward that the mechanism of "hybridization followed by chromosome doubling" would enable the survival and development of the hybrid zygote by providing each chromosome with a homolog with which to pair. However, to date there is only scant empirical evidence supporting this theory. In our previous study, interspecific-interploid crosses between the tetraploid Hylocereus megalanthus, as the female parent, and the diploid H. undatus, as the male parent, yielded only allopentaploids, allohexaploids, and 5x-and 6x-aneuploids instead of the expected allotriploids. No viable hybrids were obtained from the reciprocal cross. Since H. undatus underwent normal meiosis with regular pairing in the pollen mother cells and only reduced pollen grains were observed, the allohexaploids obtained supported the concept of "chromosome doubling." In this work, we report ploidy level, fruit morphology, and pollen viability and diameter in a group of putative hybrids obtained from an embryo rescue procedure following controlled H. megalanthus × H. undatus crosses, with the aim to elucidate, for the first time, the timing and developmental stage of the chromosome doubling. As in our previous report, no triploids were obtained, but tetraploids, pentaploids, hexaploids, and 5x-and 6xaneuploids were found in the regenerated plants. The tetraploids exhibited the morphological features of the maternal parent and could not be considered true hybrids. Based on our previous studies, we can assume that the pentaploids were a result of a fertilization event between one unreduced (2n) female gamete from the tetraploid H. megalanthus and a normal (n) haploid male gamete from H. undatus. All the allohexaploids obtained from the embryo rescue technique where those that regenerated from fertilized ovules 10 days after pollination (at the pro-embryo stage), showing that the chromosome doubling event occurred at a very early development stage, i.e., at the zygote stage or shortly after zygote formation. These allohexaploids thus constitute empirical evidence of "hybridization followed by chromosome doubling."