Statins and pancreatic cancer

Abstract

Abstract. Pancreatic cancer remains among the most lethal cancers, despite ongoing advances in treatment for all stages of the disease. Disease prevention represents another opportunity to improve patient outcome, with metabolic syndrome and its components, such as diabetes, obesity and dyslipidemia, having been recognized as modifiable risk factors for pancreatic cancer. In addition, statins have been shown to potentially reduce pancreatic cancer risk and to improve survival in patients with a combination of metabolic syndrome and pancreatic cancer. Furthermore, preclinical studies have demonstrated that statins exhibit antitumor effects in pancreatic cancer cell lines in vitro and animal models in vivo, in addition to delaying the progression of pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma (PDAC) and inhibiting PDAC formation in conditional K-Ras mutant mice. The mechanisms by which statins produce anticancer effects remain poorly understood, although appear to involve inhibition of the mevalonate/cholesterol synthesis pathway, thus blocking the synthesis of intermediates important for prenylation and activation of the Ras/mitogen-activated protein kinase 1 signaling pathway. Furthermore, statins have been identified to modulate the phosphoinositide 3-kinase/Akt serine/threonine kinase 1 and inflammation signaling pathways, and to alter the expression of genes involved in lipid metabolism, which are important for PDAC growth and proliferation. In addition, statins have been demonstrated to exhibit further antitumor mechanisms in a number of other cancer types, which are beyond the scope of the present review. In the present review, current evidence highlighting the potential of statins as chemopreventive agents in pancreatic cancer is presented, and the antitumor mechanisms of statins elucidated thus far in this disease are discussed.

Statins and pancreatic cancer risk in patients with chronic pancreatitis: A Danish nationwide population‐based cohort study

“…Furthermore, the potential anticancer effect of statins may differ according to statin solubility (i.e., lipophilic or hydrophilic), which our study was not large enough to examine. In addition, statins may elicit their anticancer effect by inhibiting the Ras cellular pathway . The Ras pathway is activated by a K ‐ras mutation, which is prevalent in nearly all pancreatic cancers and occurs at an early stage of malignant transformation .…”

“…In addition, statins may elicit their anticancer effect by inhibiting the Ras cellular pathway. 43 The Ras pathway is activated by a K-ras mutation, which is prevalent in nearly all pancreatic cancers and occurs at an early stage of malignant transformation. 34 However, a substantial proportion of chronic pancreatitis patients also harbor K-ras mutations, 44,45 precluding an inhibitory effect of statins on such a mutation.…”

Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis

“…Tumors arising from the 6419c5 cell line, on the other hand, recruit few T cells and numerous MDSCs and are highly resistant to chemotherapy and immunotherapy (37). Notably, both statins and BET inhibitors can affect not only cancer cells but also immune cells, potentially contributing to their anticancer effects (65)(66)(67)(68). Future studies aimed at elucidating how the tumor microenvironment affects responses to these drugs will aid in identifying the most appropriate contexts and strategies for use of these inhibitors.…”

Inhibition of mutant Kras and p53‐driven pancreatic carcinogenesis by atorvastatin: Mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53

“…[20][21][22] The mechanism by which statins produce anticancer effects remains elusive, though the mechanism could involve the inhibition of the mevalonate pathway, blocking the synthesis of intermediates important for protein prenylation and altering the expression of genes involved in lipid metabolism, which are important for pancreatic carcinogenesis. 23 In the present study, we continue our previously published work (in Molecular Carcinogenesis) on the use of atorvastatin to inhibit pancreatic carcinogenesis and increase survival in the LSL-Kras G12D -LSL-Trp53 R172H -Pdx1-Cre pancreatic cancer mouse model. 24 We further demonstrate (a) a significant reduction of mutant p53 positive cells in early onset pancreatitis foci, mouse pancreas intraepithelial neoplasia lesions (mPanINs), and adenocarcinoma in LSL-Kras G12D -LSL-Trp53 R172H -Pdx1-Cre mice; (b) atorvastatin treatment in mouse pancreatic cancer cells (obtained from LSL-Kras G12D -LSL-Trp53 R172H -Pdx1-Cre mice) induces degradation of mutant p53, resulting in cell-cycle arrest and apoptosis; and (c) mechanistically, reduction of DNAJA1 farnesylation by atorvastatin or a farnesyltransferase inhibitor or by small interfering RNA (siRNA) gene knockdown, or C394S mutant DNAJA1 (in which the cysteine of the CAAX box is mutated to serine, is no longer able to be farnesylated) impairs its binding and nuclear export of mutant p53, further degrading mutant p53.…”