Sustained activation of Akt kinase acts as a focal regulator to increase cell growth and survival, which cause tumorigenesis including breast cancer. Statins, potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, display anticancer activity. The molecular mechanisms by which statins block cancer cell growth are poorly understood. We demonstrate that in the tumors derived from MDA-MB-231 human breast cancer cell xenografts, simvastatin significantly inhibited phosphorylation of Akt with concomitant attenuation of expression of the anti-apoptotic protein BclXL. In many cancer cells, BclXL is a target of NFκB. Simvastatin inhibited the DNA binding and transcriptional activities of NF κ B resulting in marked reduction in transcription of BclXL. Signals transmitted by anti-neoplastic mechanism implanted in the cancer cells serve to obstruct the initial outgrowth of tumors. One such mechanism represents the action of the tumor suppressor protein PTEN, which negatively regulates Akt kinase activity. We provide the first evidence for significantly increased levels of PTEN in the tumors of simvastatin-administered mice. Importantly, simvastatin markedly prevented binding of NFκB to the two canonical recognition elements, NFRE-1 and NFRE-2 present in the PTEN promoter. Contrary to the transcriptional suppression of BclXL, simvastatin significantly increased the transcription of PTEN. Furthermore, expression of NFκ B p65 subunit inhibited transcription of PTEN, resulting in reduced protein expression, which leads to enhanced phosphorylation of Akt. Taken together, our data present a novel bifaceted mechanism where simvastatin acts on a nodal transcription factor NFκ B, which attenuates the expression of anti-apoptotic BclXL and simultaneously derepresses the expression of anti-proliferative/proapoptotic tumor suppressor PTEN to prevent breast cancer cell growth.

Substantial data from clinical trials and epidemiological studies show promising results for use of statins in many cancers, including mammary carcinoma. Breast tumor primarily metastasizes to bone to form osteolytic lesions, causing severe pain and pathological fracture. Here, we report that simvastatin acts as an inhibitor of osteolysis in a mouse model of breast cancer skeletal metastasis of human mammary cancer cell MDA-MB-231, which expresses the mutant p53R280K. Simvastatin and lovastatin attenuated migration and invasion of MDA-MB-231 and BT-20 breast tumor cells in culture. Acquisition of phenotype to express the cancer stem cell marker, CD44, leads to invasive potential of the tumor cells. Interestingly, statins significantly decreased the expression of CD44 protein via a transcriptional mechanism. shRNA-mediated down-regulation of CD44 markedly reduced the migration and invasion of breast cancer cells in culture. We identified that in the MDA-MB-231 cells, simvastatin elevated the levels of mutated p53R280K, which was remarkably active as a transcription factor. shRNAderived inhibition of mutant p53R280K augmented the expression of CD44, leading to increased migration and invasion. Finally, we demonstrate an inverse correlation between expression of p53 and CD44 in the tumors of mice that received simvastatin. Our results reveal a unique function of statins, which foster enhanced expression of mutant p53R280K to prevent breast cancer cell metastasis to bone.Statins are potent inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway for the biosynthesis of cholesterol (1). These compounds have been used for decades as safe and effective drugs in the control of hypercholesterolemia. The mevalonate pathway also produces a number of important end products, which include isoprenoid precursors, ubiquinone, dolichol, and isopentenyladenine (2). Statins also show anti-carcinogenic effects in rodent models of lung, prostate, melanoma, colon, glioma, and mammary tumorigenesis, and beneficial effects of statins have been seen in different cancers, including breast cancer (2, 3). For example, a significant 20% reduction in overall cancer risk was observed in patients with statin use (4). A recent study conducted in women who used statins showed significantly reduced risk of breast cancer as compared with nonusers (5). Moreover, an independent study of women who used statins for more than 4 years reported a significantly lower risk of breast cancer in this group (6).Several distinct mechanisms have been proposed whereby statins block tumor cell proliferation and induce apoptosis. For example, inhibition of geranylgeranyl pyrophosphate and farnesyl pyrophosphate production by statins prevents the post-translational modification of Rho and Ras GTPases necessary for their membrane localization (2). Rho proteins regulate the proliferative and invasive potential of various tumor cells, including breast cancer cells (2). Thus, suppression of geranylge...

The human papillomavirus (HPV) type 16 (HPV16) E6 protein can stimulate mechanistic target of rapamycin complex 1 (mTORC1) signaling and cap-dependent translation through activation of the PDK1 and mTORC2 kinases. Here we report that HPV18 E6 also enhances cap-dependent translation. The integrity of LXXLL and PDZ protein binding domains is important for activation of cap-dependent translation by high-risk mucosal HPV E6 proteins. Consistent with this model, low-risk mucosal HPV6b and HPV11 E6 proteins, which do not contain a PDZ protein binding motif, also activate cap-dependent translation and mTORC1, albeit at a lower efficiency than high-risk HPV E6 proteins. In contrast, cutaneous HPV5 and HPV8 E6 proteins, which lack LXXLL and PDZ motif protein binding, do not enhance cap-dependent translation. Mutagenic analyses of low-risk HPV E6 proteins revealed that association with the LXXLL motif containing ubiquitin ligase E6AP (UBE3A) correlates with activation of cap-dependent translation. Hence, activation of mTORC1 and cap-dependent translation may be important for the viral life cycle in specific epithelial tissue types and contribute to cellular transformation in cooperation with other biological activities of high-risk HPV E6-containing proteins.H uman papillomaviruses (HPVs) are small double-stranded DNA viruses with a tropism for mucosal and cutaneous epithelial cells. Over 200 HPV types have been identified, of which approximately 30 infect mucosal epithelia. Mucosal HPV types are further categorized by their propensity to cause lesions that can progress to carcinogenesis. Low-risk mucosal HPV types, including HPV type 6b (HPV6b) and HPV11, are most frequently associated with benign genital warts, whereas high-risk mucosal HPV types, such as HPV16 and HPV18, cause squamous intraepithelial lesions that can progress to cancer. High-risk HPVs are associated with over 99% of cervical cancers and at a lower prevalence with other anogenital cancers. High-risk HPV infections also account for approximately 25% of all oral cancers, particularly those of the oropharynx and tonsil (reviewed in references 15 and 23). HPV-induced cervical carcinogenesis is often associated with viral genome integration into host chromosomal DNA, causing dysregulated HPV E6 and E7 expression. The high-risk HPV E6 and E7 proteins are sufficient for the induction and maintenance of transformation of cervical epithelial cells in culture and cause cancers in transgenic mouse models (reviewed in reference 15). These proteins lack intrinsic enzymatic and nucleic acid binding activities and, therefore, modulate cellular processes through the association with and functional modification of cellular protein complexes.The best-characterized cellular targets of high-risk HPV E6 and E7 proteins are the p53 and retinoblastoma (pRB) tumor suppressors, respectively (reviewed in references 7 and 16). High-risk HPV E6 proteins form a tripartite complex with p53 and the cellular ubiquitin ligase E6AP (UBE3A), targeting p53 for ubiquitination and proteaso...