We hypothesized that the tolerance for nutrient deprivation as well as angiogenesis might be an important factor for tumor progression under hypovascular conditions. When normal human fibroblasts were subjected to extreme nutrient starvation by culturing in a medium without serum, glucose, and amino acids, cells died within 24 h. When substituted with liver cancer cell lines HepG2, Hep3B, HLE, and HuH-7, cell death occurred within 36 h. In contrast, four of six pancreas cancer cell lines, PANC-1, AsPC-1, BxPC-1, and KP-3, survived for remarkably longer periods; >50% of the cells survived, even after starvation for 48 h. Among three gastric cancer cell lines, MKN28, MKN45, and MKN74, only the most poorly differentiated MKN45 cells survived >36 h. More than 50% of the cells in colon cancer cell lines SW480, WiDr, and DLD-1 survived after 36 h, and the most undifferentiated SW480 cell line survived longest. We examined the possible involvement of PKB/Akt expression in the survival of various cell lines under nutrient starvation conditions. High expression of PKB/Akt was found to be associated with tolerance for nutrient starvation. When Akt antisense RNA expression vectors were introduced into PANC-1 cells, the tolerance was partially but significantly diminished by vectors for Akt1 and Akt2 but not Akt3. Because elimination of the tolerance might serve as a new strategy for cancer therapy, several compounds were tested for this purpose, and troglitazone, an insulin sensitizer, as well as LY294002, a phosphatidylinositol 3-kinase inhibitor, were found to kill PANC-1 cells only under nutrient starvation conditions.

https://cancerres.aacrjournals.org/content/canres/60/21/6201.full.pdf

Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy

Angiogenesis is the process of new capillary formation from previously existing mature vessels. The adult ovary exhibits dramatic growth and regression of capillary networks on a cyclic basis. Ovarian follicles and the corpus luteum contain and produce endothelial cell-specific factors, which may act alone or in concert to regulate the process of angiogenesis. These factors are ultimately controlled by endocrine, paracrine and autocrine regulation, as well as by metabolic cellular signals such as intracellular oxygen content and ageing. Aberrant production of these angiogenic factors may be the cause of vascular dysfunction and the development of ovarian disorders. Recent technological advances for monitoring blood flow and measuring angiogenic factors could assist in accurately diagnosing ovarian disorders. Further elucidation of specific physiological role(s) of factors involved in angiogenesis of the pre-ovulatory follicle and developing corpus luteum may be useful in addressing issues of infertility in women.

Angiogenesis in ovarian follicular and luteal development.

As a member of the vertebrate-specific secreted ribonucleases, angiogenin (ANG) was first isolated and identified solely by its ability to induce new blood vessel formation, and now, it has been recognized to play important roles in various physiological and pathological processes through regulating cell proliferation, survival, migration, invasion, and/or differentiation. ANG exhibits very weak ribonucleolytic activity that is critical for its biological functions, and exerts its functions through activating different signaling transduction pathways in different target cells. A series of recent studies have indicated that ANG contributes to cellular nucleic acid metabolism. Here, we comprehensively review the results of studies regarding the structure, mechanism, and function of ANG over the past three decades. Moreover, current problems and future research directions of ANG are discussed. The understanding of the function and mechanism of ANG in a wide context will help to better delineate its roles in diseases, especially in cancer and neurodegenerative diseases.

Three decades of research on angiogenin: a review and perspective.

Both tolerance to nutrient starvation and angiogenesis are esse tial for cancer progression because of the insufficient supply of nutrients to tumor tissue. Since chronic nutrient starvation seldom occurs in normal tissue, cancer's tolerance to nutrient starvation should provide a novel target for cancer therapy. In this study, we propose an anti-austerity strategy to exploit the ability of agents to eliminate cancer cells' tolerance to nutrient starvation. We established a simple screening method for agents that inhibit cancer cell viability preferentially during nutrient starvation, using PANC-1 cell line cultured in nutrient-rich and nutrien deprived media. After screening over 2000 culture media of act nomycetes, we identified a new compound, kigamicin (C48H59NO19), which shows preferential cytotoxicity to cancer ceels under nutrient-deprived conditions, but hardly any cytotoxici under nutrient-rich conditions. Both subcutaneous and oral a ministration of kigamicin D strongly suppressed the tumor growth of several tested pancreatic cancer cell lines in nude mice Moreover, kigamicin D was observed to block the activation of Akt induced by nutrient starvation. Therefore, our results sugge that kigamicin D be a candidate for implementing our novel concept, anti-austerity, which may serve as a new strategy for cancer therapy.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2004.tb03247.x

Kigamicin D, a novel anticancer agent based on a new anti-austerity strategy targeting cancer cells' tolerance to nutrient starvation.

In humans, the ribonuclease A (RNase A) superfamily contains eight different members that have RNase activities, and all of these members are encoded on chromosome 14. The proteins are secreted by a large variety of different tissues and cells; however, a comprehensive understanding of these proteins’ physiological roles is lacking. Different biological effects can be attributed to each protein, including antiviral, antibacterial and antifungal activities as well as cytotoxic effects against host cells and parasites. Different immunomodulatory effects have also been demonstrated. This review summarizes the available data on the human RNase A superfamily and illustrates the significant role of the eight canonical RNases in inflammation and the host defence system against infections.

The Ribonuclease A Superfamily in Humans: Canonical RNases as the Buttress of Innate Immunity

Angiogenin is involved in morphological changes and angiogenesis in the ovary.

The electroless nickel plating on an aluminum input/output (I/O) pad was investigated. The aluminum pad was pretreated in a zincate solution prior to electroless nickel plating. Zinc particles on the aluminum pad gave a good adherent nickel layer. The adhesion and uniformity of zinc on the aluminum is the key factor in under-bump metallurgy (UBM). The electrode potential changes with and without zinc ions in the bath were measured to analyze the sequence of two competing reactions: zinc deposit and hydrogen evolution. The relationship between aluminum dissolution and the ratio of zinc and NaOH was investigated. The electroless nickel deposition rate was dependent on bath composition. The effects of complexing ligand and additive on the nickel deposit were analyzed. Electrode potential changes were measured with time to confirm nucleation and grain growth. Adhesion of the UBM was related to zinc-particle dissolution and nickel nucleation. The uniform nickel UBM was fabricated on a real Al I/O pad.

In-se Lee

Papers

Angiogenin is involved in morphological changes and angiogenesis in the ovary.

The Effects of Bath Composition on the Morphologies of Electroless Nickel Under-Bump Metallurgy on Al Input/ Output Pad

The existence of substance P in Purkinje cells in cerebellum of the gerbil