Brain mitochondrial dysfunction is hallmark pathology of Alzheimer’s disease (AD). Recently, the role of synaptosomal mitochondrial dysfunction in the development of synaptic injury in AD has received increasing attention. Synaptosomal mitochondria are a subgroup of neuronal mitochondria specifically locating at synapses. They play an essential role in fueling synaptic functions by providing energy on the site; and their defects may lead to synaptic failure, which is an early and pronounced pathology in AD. In our previous studies we have determined early synaptosomal mitochondrial dysfunction in an AD animal model (J20 line) overexpressing human Amyloid beta (Aβ), the key mediator of AD. In view of the limitations of J20 line mice in representing the full aspects of amyloidopathy in AD cases, we employed 5xFAD mice which are thought to be a desirable paradigm of amyloidopathy as seen in AD subjects. In addition, we have also examined the status of synaptosomal mitochondrial dynamics as well as Parkin-mediated mitophagy which have not been previously investigated in this mouse model. In comparison to nontransgenic (nonTg mice), 5xFAD mice demonstrated prominent synaptosomal mitochondrial dysfunction. Moreover, synaptosomal mitochondria from the AD mouse model displayed imbalanced mitochondrial dynamics towards fission along with activated Parkin and LC3BII recruitment correlating to spatial learning & memory impairments in 5xFAD mice in an age-dependent manner. These results suggest that synaptosomal mitochondrial deficits are primary pathology in Aβ-rich environments and further confirm the relevance of synaptosomal mitochondrial deficits to the development of AD.

Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM). CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G cell cycle arrest and caspase-dependent apoptosis. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. Given that immunomodulatory drugs (IMiDs) stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with IMiDs show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4 and MYC, providing a rationale for clinical testing of this drug combination in MM patients.

Estrogen receptor α (ERα)low/− tumors are associated with breast cancer (BCa) endocrine resistance, where ERα low tumors show a poor prognosis and a molecular profile similar to triple negative BCa tumors. Interleukin‐1 (IL‐1) downregulates ERα accumulation in BCa cell lines, yet the cells can remain viable. In kind, IL‐1 and ERα show inverse accumulation in BCa patient tumors and IL‐1 is implicated in BCa progression. IL‐1 represses the androgen receptor hormone receptor in prostate cancer cells concomitant with the upregulation of the prosurvival, autophagy‐related protein, Sequestome‐1 (p62/SQSTM1; hereinafter, p62); and given their similar etiology, we hypothesized that IL‐1 also upregulates p62 in BCa cells concomitant with hormone receptor repression. To test our hypothesis, BCa cell lines were exposed to conditioned medium from IL‐1‐secreting bone marrow stromal cells (BMSCs), IL‐1, or IL‐1 receptor antagonist. Cells were analyzed for the accumulation of ERα, progesterone receptor (PR), p62, or the autophagosome membrane protein, microtubule‐associated protein 1 light chain 3 (LC3), and for p62‐LC3 interaction. We found that IL‐1 is sufficient to mediate BMSC‐induced ERα and PR repression, p62 and autophagy upregulation, and p62‐LC3 interaction in ERα+/PR+ BCa cell lines. However, IL‐1 does not significantly elevate the high basal p62 accumulation or high basal autophagy in the ERα−/PR− BCa cell lines. Thus, our observations imply that IL‐1 confers a prosurvival ERα−/PR− molecular phenotype in ERα+/PR+ BCa cells that may be dependent on p62 function and autophagy and may underlie endocrine resistance.

Pan proviral integrations of Moloney virus (PIM) inhibition in multiple myeloma (MM) results in reduced cell viability in tested human-derived MM cell lines and reduces tumor burden in xenograft mouse models, making PIMs important therapeutic targets for the disease. PIM kinase inhibitors are currently being tested clinically in MM. We sought to elucidate the role of the various PIMs in MM. Our data demonstrate that Pim2 has a significant role in MM cell cytotoxicity. Our data provide evidence for a novel role for Pim2 in the regulation of the DNA damage response (DDR). Knockdown of Pim2 upregulates several downstream DDR markers, mimicking the effects of doxorubicin (Dox) treatment of MM cells, and suggesting a role for the kinase as a negative regulator of this pathway. Dox-induced DNA damage results in a decrease in Pim2 levels, placing the kinase directly downstream of the site of Dox-DNA binding. Overexpression of Pim2 confers a slight survival advantage against Dox through antiapoptotic activity, further underscoring its relevance in the DDR pathway. These data provide insights into a novel mechanism of PIM kinase activity and provide the framework for designing therapeutic approaches in MM.