KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of both an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.

Associations of multiple metals with kidney outcomes in lead workers.

OBJECTIVES: Environmental exposure to multiple metals is common. A number of metals cause nephrotoxicity with acute and/or chronic exposure. However, few epidemiologic studies have examined the impact of metal coexposure on kidney function. Therefore, the authors evaluated associations of antimony and thallium with kidney outcomes and assessed the impact of cadmium exposure on those associations in lead workers. METHODS: Multiple linear regression was used to examine associations between ln-urine thallium, antimony and cadmium levels with serum creatinine- and cystatin-C-based glomerular filtration measures and ln-urine N-acetyl-ß-D-glucosaminidase (NAG). RESULTS: In 684 participants, median urine thallium and antimony were 0.39 and 0.36 µg/g creatinine, respectively. After adjustment for lead dose, urine creatinine and kidney risk factors, higher ln-urine thallium was associated with higher serum creatinine- and cystatin-C-based estimates of glomerular filtration rate; associations remained significant after adjustment for antimony and cadmium (regression coefficient for serum creatinine-based estimates of glomerular filtration rate =5.2 ml/min/1.73 m2; 95% CI =2.4 to 8.0). Antimony associations with kidney outcomes were attenuated by thallium and cadmium adjustment; thallium and antimony associations with NAG were attenuated by cadmium. CONCLUSIONS: Urine thallium levels were significantly associated with both serum creatinine- and cystatin-C-based glomerular filtration measures in a direction opposite that expected with nephrotoxicity. Given similarities to associations recently observed with cadmium, these results suggest that interpretation of urine metal values, at exposure levels currently present in the environment, may be more complex than previously appreciated. These results also support multiple metal analysis approaches to decrease the potential for inaccurate risk conclusions.

Uranium associations with kidney outcomes vary by urine concentration adjustment method.

Uranium is a ubiquitous metal that is nephrotoxic at high doses. Few epidemiologic studies have examined the kidney filtration impact of chronic environmental exposure. In 684 lead workers environmentally exposed to uranium, multiple linear regression was used to examine associations of uranium measured in a 4-h urine collection with measured creatinine clearance, serum creatinine- and cystatin-C-based estimated glomerular filtration rates, and N-acetyl-ß-D-glucosaminidase (NAG). Three methods were utilized, in separate models, to adjust uranium levels for urine concentration--µg uranium/g creatinine; µg uranium/l and urine creatinine as separate covariates; and µg uranium/4 h. Median urine uranium levels were 0.07 µg/g creatinine and 0.02 µg/4 h and were highly correlated (rs=0.95). After adjustment, higher ln-urine uranium was associated with lower measured creatinine clearance and higher NAG in models that used urine creatinine to adjust for urine concentration but not in models that used total uranium excreted (µg/4 h). These results suggest that, in some instances, associations between urine toxicants and kidney outcomes may be statistical, due to the use of urine creatinine in both exposure and outcome metrics, rather than nephrotoxic. These findings support consideration of non-creatinine-based methods of adjustment for urine concentration in nephrotoxicant research.