Elevated K-ras activity with cholestyramine and lovastatin, but not konjac mannan or niacin in lung—–Importance of mouse strain

Abstract

Our previous work established that hypocholesterolemic agents altered K-ras intracellular localization in lung. Here, we examined K-ras activity to define further its potential importance in lung carcinogenesis. K-ras activity in lungs from male A/J, Swiss and C57BL/6 mice was examined. For three weeks, mice consumed either 2 or 4% cholestyramine (CS), 1% niacin, 5% konjac mannan (KM), or were injected with lovastatin 25 mg/kg three or five times weekly (Lov-3X and Lov-5X). A pair-fed (PF) group was fed the same quantity of diet consumed by the Lov-5X mice to control for lower body weights in Lov-5X mice. After three weeks, serum cholesterol was assayed with a commercial kit. Activated K-ras protein from lung was affinity precipitated with a Raf-1 ras binding domain-glutathione-S-transferase fusion protein bound to glutathione-agarose beads, followed by Western blotting, K-ras antibody treatment, and chemiluminescent detection. Only KM reduced serum cholesterol (in 2 of 3 mouse strains). In C56BL/6 mice treated with Lov-3X, lung K-ras activity increased 1.8-fold versus control (p = 0.009). In normal lung with wild-type K-ras, this would be expected to be associated with maintenance of differentiation. In A/J mice fed 4% CS, K-ras activity increased 2.1-fold (p = 0.02), which might be responsible for the reported enhancement of carcinogenesis in carcinogen-treated rats fed CS. KM feeding and PF treatment had no significant effects on K-ras activity. These data are consistent with the concept that K-ras in lung has an oncogenic function when mutated, but may act as a tumor suppressor when wild-type.

Cassava starch–konjac glucomannan biodegradable blend films: In vitro study as a matrix for controlled drug delivery

“…Pathak et al 13 developed a multi block biodegradable hydrogel for drug delivery and tissue treatment in which the hydrophilic block was konjac glucomannan. Thus, both starch and KGM have been recognized individually for their great potential 14, 15. Natural polymers are normally high MW materials and generally swell slowly to their equilibrium 16.…”

Plasma membrane regulates Ras signaling networks

“…If K-Ras localization and function in the plasma membrane is nucleotide-dependent, like it is for H-Ras, then specific regulation of K-Ras-GTP by drugs altering the membrane composition may provide a possible anti-cancer therapeutic approach. [51][52][53] Membrane microdomains change the access of Ras to its binding partners Ras proteins have different degrees of access to GEFs, GAPs, and effectors in various microdomains. 54 This differential access idea (graphically shown in Fig.…”