Early determination of potential critical quality attributes of therapeutic antibodies in developability studies through surface plasmon resonance-based relative binding activity assessment.

Precise measurement of the binding activity changes of therapeutic antibodies is important to determine the potential critical quality attributes (CQAs) in developability assessment at the early stage of antibody development. Here, we report a surface plasmon resonance (SPR)-based relative binding activity method, which incorporates both binding affinity and binding response and allows us to determine relative binding activity of antibodies with high accuracy and precision. We applied the SPR-based relative binding activity method in multiple forced degradation studies of antibody developability assessment.

A comprehensive review of pancreatic cancer and its therapeutic challenges.

Pancreatic cancer is a devastating and lethal human malignancy with no curable chemo-treatments available thus far. More than 90% of pancreatic tumors are formed from ductal epithelium as pancreatic ductal adenocarcinoma (PDAC), which often accompany with the expression of mutant . The incidences of pancreatic cancer are expected to increase rapidly worldwide in the near future, due to environmental pollution, obesity epidemics and etc.

PKC is an indispensable factor in promoting environmental toxin chromium-mediated transformation and drug resistance.

Hexavalent chromium [Cr(VI)] pollution is a serious environmental problem, due to not only its toxicity but also carcinogenesis. Although studies reveal several features of Cr(VI)-induced carcinogenesis, the underlying mechanisms of how Cr(VI) orchestrates multiple mitogenic pathways to promote tumor initiation and progression remain not fully understood. Src/Ras and other growth-related pathways are shown to be key players in Cr(VI)-initiated tumor prone actions.

Glia-derived temporal signals orchestrate neurogenesis in the mushroom body.

Intrinsic mechanisms such as temporal series of transcription factors orchestrate neurogenesis from a limited number of neural progenitors in the brain. Extrinsic regulations, however, remain largely unexplored. Here we describe a two-step glia-derived signal that regulates neurogenesis in the mushroom body (MB).

Ras sumoylation in cell signaling and transformation.

Ras proteins are small GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, and differentiation. Mutations or deregulated activities of Ras are frequently the driving force for oncogenic transformation and tumorigenesis. Posttranslational modifications play a crucial role in mediating the stability, activity, or subcellular localization/trafficking of numerous cellular regulators including Ras proteins.

The F-Box Protein CG5003 Regulates Axon Pruning and the Integrity of the Mushroom Body.

Protein homeostasis serves as an important step in regulating diverse cellular processes underlying the function and development of the nervous system. In particular, the ubiquitination proteasome system (UPS), a universal pathway mediating protein degradation, contributes to the development of numerous synaptic structures, including the olfactory-associative learning center mushroom body (MB), thereby affecting associated function. Here, we describe the function of a newly characterized F-box protein CG5003, an adaptor for the RING-domain type E3 ligase (SCF complex), in MB development.

Transcription factor Sp1 is upregulated by PKCι to drive the expression of YAP1 during pancreatic carcinogenesis.

Recently, we identified that the atypical protein kinase C isoform ι (PKCι) enhances the expression of Yes-associated protein 1 (YAP1) to promote the tumorigenesis of pancreatic adenocarcinoma harboring mutant KRAS (mu-KRAS). To advance our understanding about underlying mechanisms, we analyze the transcription of YAP1 in pancreatic cancer cells and reveal that transcription factor specificity protein 1 (Sp1) is upregulated by PKCι and subsequently binds to multiple sites in YAP1 promoter to drive the transactivation of YAP1 in pancreatic cancer cells carrying mu-KRAS. The bioinformatics analysis further substantiates that the expression of PKCι, Sp1 and YAP1 is correlated and associated with the stages and prognosis of pancreatic tumors.

Protein phase separation and its role in tumorigenesis.

Cancer is a disease characterized by uncontrolled cell proliferation, but the precise pathological mechanisms underlying tumorigenesis often remain to be elucidated. In recent years, condensates formed by phase separation have emerged as a new principle governing the organization and functional regulation of cells. Increasing evidence links cancer-related mutations to aberrantly altered condensate assembly, suggesting that condensates play a key role in tumorigenesis.

Nicotine exposure potentiates lung tumorigenesis by perturbing cellular surveillance.

Background: Nicotine is a major tobacco component and found at circulating concentrations in smokers' bloodstreams. Although considered a non-carcinogenic substance, nicotine rapidly defuses to tissues after being inhaled, inviting effects on cellular physiology, particularly in the lung. Widespread increased use of nicotine-based e-cigarettes, especially in younger adults, creates an urgent need for improved understanding of nicotine's potential to impact human health.

Mu-KRAS attenuates Hippo signaling pathway through PKCι to sustain the growth of pancreatic cancer.

The atypical protein kinase C isoform ι (PKCι) is upregulated, which cooperates with mutated KRAS (mu-KRAS) to promote the development of pancreatic cancers. However, the exact role of PKCι in KRAS-mediated pancreatic tumorigenesis is not fully defined. In the present study, we demonstrate that mu-KRAS upregulates and activates PKCι, accompanied by dephosphorylation of large tumor suppressor (LATS), a key member of the growth-inhibiting Hippo signaling pathway.

Chronic low dose arsenic exposure preferentially perturbs mitotic phase of the cell cycle.

Environmental pollution is a big challenge for human survival. Arsenic compounds are well-known biohazard, the exposure of which is closely linked to onsets of various human diseases, particularly cancers. Upon chronically exposing to arsenic compounds, genomic integrity is often disrupted, leading to tumor development.

Nicotine exposure induces the proliferation of oral cancer cells through the α7 subunit of the nicotinic acetylcholine receptor.

Oral cancer and smoking are closely related, because the oral cavity, which is the route of ingestion of tobacco smoke, is in direct contact with the oral mucosa. Nicotine, one of the components of tobacco, can diffuse rapidly to the central nervous system and is responsible for tobacco addiction. Nicotine is present in high concentrations in the bloodstream of smokers; while the addictive effects of this alkaloid have extensively been studied, its effect on tumorigenesis is not clear yet.

PKCι and YAP1 are crucial in promoting pancreatic tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant disease with 5-year survival rate of less than 6%. Activating mutations of () are often detected in most of PDAC patients. Although it has been known that oncogenic is the driver of pancreatic cancer initiation and development, the underlying mechanisms by which promotes PDAC remain poorly understood.

ISO, via Upregulating MiR-137 Transcription, Inhibits GSK3β-HSP70-MMP-2 Axis, Resulting in Attenuating Urothelial Cancer Invasion.

Our most recent studies demonstrate that miR-137 is downregulated in human bladder cancer (BC) tissues, while treatment of human BC cells with isorhapontigenin (ISO) elevates miR-137 abundance. Since ISO showed a strong inhibition of invasive BC formation in the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced invasive BC mouse model, the elucidation of a potential biological effect of miR-137 on antagonizing BC invasion and molecular mechanisms underlying ISO upregulation of miR-137 are very important. Here we discovered that ectopic expression of miR-137 led to specific inhibition of BC invasion in human high-grade BC T24T and UMUC3 cells, while miR-137 deletion promoted the invasion of both cells, indicating the inhibitory effect of miR-137 on human BC invasion.

A lethal synergy induced by phellinus linteus and camptothecin11 in colon cancer cells.

Side effects of anti-cancer drugs are always challenging for effective cancer treatments. The polysaccharides extracted from (PLGL) have been widely used in treating cancers. However, the mechanism by which PLGL antagonizes cancerous growth has not been fully investigated.

RAS GTPases are modified by SUMOylation.

RAS proteins are GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, differentiation, and autophagy. Mutations or deregulated activities of RAS are frequently the driving force for oncogenic transformation and tumorigenesis. Given the important roles of the small ubiquitin-related modifier (SUMO) pathway in controlling the stability, activity, or subcellular localization of key cellular regulators, we investigated here whether RAS proteins are posttranslationally modified ( SUMOylated) by the SUMO pathway.

RhoGDIβ promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation.

Our most recent studies demonstrate that RhoGDIβ is able to promote human bladder cancer (BC) invasion and metastasis in an X-link inhibitor of apoptosis protein-dependent fashion accompanied by increased levels of matrix metalloproteinase (MMP)-2 protein expression. We also found that RhoGDIβ and MMP-2 protein expressions are consistently upregulated in both invasive BC tissues and cell lines. In the present study, we show that knockdown of RhoGDIβ inhibited MMP-2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of RhoGDIβ upregulated MMP-2 protein expression and promoted invasion as well.

Suppression of PKC causes oncogenic stress for triggering apoptosis in cancer cells.

Gain of functional mutations in ras occurs in more than 30% of human malignancies and in particular 90% of pancreatic cancer. Mutant ras, via activating multiple effector pathways, not only promote cell growth or survival, but also apoptosis, depending upon cell types or circumstances. In order to further study the mechanisms of apoptosis induced by oncogenic ras, we employed the ras loop mutant genes and demonstrated that Akt functioned downstream of Ras in human pancreatic cancer or HPNE cells ectopically expressing mutated K-ras for the induction of apoptosis after the concurrent suppression of PKC α and β.

Molecular Chaperone Calnexin Regulates the Function of Sodium Channel Paralytic.

Neuronal activity mediated by voltage-gated channels provides the basis for higher-order behavioral tasks that orchestrate life. Chaperone-mediated regulation, one of the major means to control protein quality and function, is an essential route for controlling channel activity. Here we present evidence that ER chaperone Calnexin colocalizes and interacts with the α subunit of sodium channel Paralytic.

Chromium IV exposure, via Src/Ras signaling, promotes cell transformation.

Hexavalent chromium [Cr(VI)] is a well-known environment carcinogen. The exposure of Cr(VI) through contaminated soil, air particles, and drinking water is a strong concern for the public health worldwide. While many studies have been done, it remains unclear which intracellular molecules transduce Cr(VI)-mediated carcinogenic signaling in cells to promote cancer.

Ral A, via activating the mitotic checkpoint, sensitizes cells lacking a functional Nf1 to apoptosis in the absence of protein kinase C.

Nf1 mutations or deletions are suggested to underlie the tumor predisposition of NF1 (neurofibromatosis type 1) and few treatments are available for treating NF1 patients with advanced malignant tumors. Aberrant activation of Ras in Nf1-deficient conditions is responsible for the promotion of tumorigenesis in NF1. PKC is proven to be an important factor in supporting the viability of Nf1-defected cells, but the molecular mechanisms are not fully understood.

Low doses of arsenic, via perturbing p53, promotes tumorigenesis.

In drinking water and in workplace or living environments, low doses of arsenic can exist and operate as a potent carcinogen. Due to insufficient understanding and information on the pervasiveness of environmental exposures to arsenic, there is an urgent need to elucidate the underlying molecular mechanisms of arsenic regarding its carcinogenic effect on human health. In this study, we demonstrate that low doses of arsenic exposure mitigate or mask p53 function and further perturb intracellular redox state, which triggers persistent endoplasmic reticulum (ER) stress and activates UPR (unfolded protein response), leading to transformation or tumorigenesis.