Loss of AMPK activation promotes the invasion and metastasis of pancreatic cancer through an HSF1‐dependent pathway

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a mortality rate that closely parallels its incidence rate, and a better understanding of the molecular and cellular mechanisms associated with the invasion and distant metastasis is required. Heat shock factor 1 (HSF1) is a very highly conserved factor in eukaryotes that regulates the protective heat shock response. Here, we show that HSF1 is abnormally activated in pancreatic cancer. The knockdown of HSF1 impaired the invasion and migration and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells in vitro; however, the upregulation of HSF1 showed the opposite effects. In vivo, the pharmacological inhibition of HSF1 significantly reduced the tumor burden, decreased the incidence of invasion, and prolonged the overall survival of transgenic mice harboring the spontaneous pancreatic cancer. We suggest that the loss of AMP‐activated protein kinase (AMPK) activation mediates the abnormal activation of HSF1 based on the findings that phospho‐HSF1 (p‐HSF1) was highly expressed in human PDAC tissues with a low expression of p‐AMPK and that in those tissues with a high p‐AMPK expression, the level of p‐HSF1 was decreased. The in vivo and in vitro activation of AMPK impaired the activity of HSF1, and HSF1 mediated the effects of the AMPK knockdown‐induced pancreatic cancer invasion and migration. Our study revealed a novel mechanism by which the loss of AMPK activation amplifies the activity of HSF1 to promote the invasion and metastasis of pancreatic cancer.

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…Indeed, it was demonstrated that HSF1 promotes TGFβ-induced EMT, tumorigenesis, and metastases in a murine breast cancer model [161]; the EMT-promoting mechanism was due to HSF1-mediated stimulation of the RAS/RAF/MEK/ERK1/2 signaling pathway. Additionally, HSF1 was found to be required for EMT in ovarian cancer (including a spheroid growth model) [162], hepatocellular carcinoma [163], and pancreatic cancer [164]. In the latter case, the abnormal HSF1 activation (phosphorylation) resulting in EMT induction in pancreatic cancer cells was correlated with the failure of AMPK activation in pancreatic tumors [164].…”

Electric field down-regulates CD9 to promote keratinocytes migration through AMPK pathway

“…Interestingly, we found that EF inactivated AMPK signaling, which was related to CD9 expression in keratinocytes. It has been indicated that AMPK pathway is involved in cell migration in many types of cancer cells [19,31], and previous study has confirmed that the inhibition of AMPK promotes the mobility of HaCaT cells [17]. Furthermore, hypoxic preconditioning also promotes the migration of keratinocytes through AMPK pathway [32,33].…”

“…Studies have shown that the activation of AMPK inhibits the migration of tongue squamous cell carcinoma cells [18]. Loss of AMPK activation promotes the invasion and metabolism in many cancers [15,19]. Recently, an AMPK activator met has been shown to reduce cell proliferation and delay wound healing [20], suggesting that AMPK may be involved in the cytobiology of keratinocytes during wound repair.…”

α‐Mangostin suppresses the de novo lipogenesis and enhances the chemotherapeutic response to gemcitabine in gallbladder carcinoma cells via targeting the AMPK/SREBP1 cascades

“…To evaluate whether MA affects the viability of GBC cells, NOZ and GBC-SD cells were incubated with a series of incremental doses of MA (0, 1, 2, 4, 6, 8, 12 and 16 μmol/L) to determine whether the effects are time-dependent. The cell viability was analysed by the assessment of the absorbance at 490 nm after 24,48 and 72 hours using the MTT assay. As shown in Figure 1A,B, MA repressed the growth of GBC cells in a time-and dose-dependent manner.…”