pp32 (ANP32A) Expression Inhibits Pancreatic Cancer Cell Growth and Induces Gemcitabine Resistance by Disrupting HuR Binding to mRNAs

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the mRNA encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy

Studies on some electrophilic substitution reactions in the furan series: the synthesis of 2,4-disubstituted furans

An investigation of several electrophilic substitution reactions on 3-methylfuran is reported. Friedel-Crafts acylation of 3-methylfuran with acetyl and propionyl chlorides yielded both 2,3- and 2,4-disubstituted furans. Vilsmeier and Gatterman formylation procedures yielded 3-methylfurfural and 4-methylfurfural while mercuration appeared to yield only the 2,3-disubstituted derivative

Synthetic studies in the Veratrum alkaloid series. II. The total synthesis of verarine, veratramine, jervine, and veratrobasine

Coupling of 3β-acetoxy-5α-etiojerv-12(13)-en-17-one (1) with the lithio derivative of 2-ethyl-5-methylpyridine provides the crucial intermediate (3) for the subsequent elaboration to verarine. Aromatization of 3 to 4 and reduction of the latter provides a mixture from which N-acetyl-5α,6-dihydroverarine (11) was isolated. Subsequent introduction of the 5,6-double bond in the latter and removal of the N-acetate function completed the synthesis of verarine (31). In a similar sequence of reactions employing 1 and the lithio derivative of 2-ethyl-3-methoxy-5-methyl-pyridine, the resultant intermediate (54), was elaborated to 5α,6-dihydroveratramine (56). Due to known conversions of the latter to veratramine (14), jervine (32), veratrobasine (33), and 11-deoxojervine (34), the formal total synthesis of these natural products is complete