Over-expressions of AMPK subunits in ovarian carcinomas with significant clinical implications

Abstract

BackgroundAMP-activated protein kinase (AMPK) has recently been considered as a potential target for cancer therapy. However, the expression status of various subunits of the heterotrimeric AMPK in human cancers is rarely reported. We decided to determine their expressions in ovarian carcinomas and their relationships with the disease.MethodsExpressions and locations of the AMPK-α1, -α2, -β1, -β2, -γ1 and -γ2 were detected by quantitative PCR (Q-PCR) and immunohistochemical staining (IHC). Their expression levels in ovarian tumors were compared with normal controls and also correlated with clinicopathological parameters.ResultsExcept AMPK-α1, expressions of the other five AMPK subunits are significantly higher in ovarian carcinomas as determined by Q-PCR. Although IHC detection of AMPK-γ1 and -γ2 were not successful, over-expressions of AMPK-α2, -β1, and -β2 were further confirmed by IHC. Over-expressions of various AMPK subunits occurred independently and were mainly detected in the cytoplasm. Interestingly, AMPK-α2 and -β1 were also detected in the nucleus and cell membrane, respectively. Clinical correlation analyses indicate that expressions of different AMPK subunits are associated with different subtypes of carcinoma. High expression of AMPK-α2 is significantly associated with endometrioid carcinomas. On the other hand, high expressions of AMPK-β and -γ subunits are associated with mucinous and serous carcinomas, respectively. Furthermore, high expressions of AMPK-β1 and -γ2 are also associated with early and late stages of disease, respectively. Finally, patients with high expression of AMPK-α2 had better prognosis.ConclusionsAberrant expressions of AMPK subunits may play important roles in ovarian carcinogenesis. Each AMPK subunit may have its own function other than just a component of the AMPK molecule. Correlations with clinical parameters suggest that expressions of AMPK subunits have different clinical implications in ovarian cancer development.

Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

“…Consistent with this finding, AMPKβ subunits appear to be confined in both the nuclear and the nonnuclear cell fractions [39,54]. Our recent study reported that AMPKβ1 is consistent with the amount of AMPK heterotrimeric complexes and the AMPK activity in advanced ovarian cancers [58]. Both functional and mechanistic studies showed that the reduced AMPKβ1 expression leads to decreased AMPK activity, but enhanced oncogenic capacities of ovarian cancer cells via modulating the AKT/ERK and JNK signaling pathways [59].…”

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

“…We have selected three potential target genes, ADRBK2 (also known as GRK3), PRKAB2 and HIPK2, which have been reportedly related to cancer [43][44][45] , for further study. Of the three genes, only ADRBK2 was found to be able to induce Huh7 cells to acquire in vitro self-renewal ability as evidenced by increased spheroid formation efficiency, as well …”

AMPK β1 reduces tumor progression and improves survival in p53 null mice

“…These include inactivating mutations in the tumor suppressors p53 and LKB1 or elevated levels of glucose (Friedrichsen et al ., 2013), insulin (Ruderman et al ., 2013), TNF (Steinberg et al ., 2006), and LPS (Galic et al ., 2011). In contrast, elevated levels of AMPK β1 have been associated with increased survival in lymphoma and ovarian cancer (Hoffman et al ., 2013; Li et al ., 2012). In the current study, we provide the first genetic evidence that deletion of the AMPK β1 isoform accelerates the progression of a T‐cell lymphoma that reduces the survival of mice that are heterozygous or homozygous null for p53.…”

“…It is also the primary subunit which is targeted by small‐molecule direct AMPK activators such as A769662 (Cool et al ., 2006; Sanders et al ., 2007; Scott et al ., 2014), MT‐63‐78 (Zadra et al ., 2014), and salicylate (Hawley et al ., 2012), all of which have been shown to reduce cancer cell proliferation in some (Huang et al ., 2008; O'Brien et al ., 2015; Zadra et al ., 2014), but not all studies (Vincent et al ., 2015). Elevated AMPK β1 expression has also been linked to increased lymphoma (Hoffman et al ., 2013) and ovarian cancer survival (Li et al ., 2012), tumor types that are commonly associated with mutations in p53. In addition the DNA‐damaging agent etoposide increases AMPK β1 expression and overexpression of AMPK β1 reduces cellular proliferation in vitro (Li et al ., 2003).…”