High PGAM5 expression induces chemoresistance by enhancing Bcl-xL-mediated anti-apoptotic signaling and predicts poor prognosis in hepatocellular carcinoma patients

Abstract

Hepatocellular carcinoma (HCC) is the one of most common and deadly cancers, and is also highly resistant to conventional chemotherapy treatments. Mitochondrial phosphoglycerate mutase/protein phosphatase (PGAM5) regulates mitochondrial homeostasis and cell death, however, little is known about its roles in cancer. The aim of this study was to explore the clinical significance and potential biological functions of PGAM5 in hepatocellular carcinoma. For the first time, our results show that PGAM5 is significantly upregulated in HCC compared with corresponding adjacent noncancerous hepatic tissues and high PGAM5 expression is an independent predictor of reduced survival times in both univariate and multivariate analyses. Additionally, in vivo and in vitro studies showed that depleting PGAM5 expression inhibited tumor growth and increased the 5-fluorouracil sensitivity of HCC cells. Conversely, restoring PGAM5 expression in PGAM5-knockdown cells dramatically enhanced HCC cell resistance to 5-fluorouracil. Importantly, we demonstrated that the mechanism of 5-fluorouracil resistance conferred to HCC cells by PGAM5 was via inhibiting BAX- and cytochrome C-mediated apoptotic signaling by interacting and stabilizing Bcl-xL. Consistently, in the same cohorts of HCC patient tissues, Bcl-xL expression was positively correlated with PGAM5, and together predicted poor prognoses. In Conclusion, Our data highlight the molecular etiology and clinical significance of PGAM5 in HCC. Targeting the novel signaling pathway mediated by PGAM5/Bcl-xL may represent a new therapeutic strategy to improve the survival outcomes of HCC patients.

Rewiring of Cancer Cell Metabolism by Mitochondrial VDAC1 Depletion Results in Time-Dependent Tumor Reprogramming: Glioblastoma as a Proof of Concept

“…The expression of PGAM5 that dephosphorylates and activates ASK1 MAP3K [144] and prolongs survival of tumor cells in hepatocellular carcinoma (HCC) [145], and PLXNB2, an activator of the GTPase Rho [56], promoting ovarian cancer cell proliferation and invasion [57] and prostate tumor growth [58], as well as ICAM1, which activates Rho [54] and which increased metastasis in pancreatic ductal adenocarcinoma [55], were reduced (5- and 16-fold). On the other hand, the expression levels of SUSD2 (Figure 10A), a Notch 3-regulating protein that also suppresses metastasis in high-grade serous ovarian carcinoma [146], and of STAT6, playing a major role in regulation of IL-4 synthesis, reducing colon inflammation during tumorigenesis but facilitating tumor formation [147], increased (150- and 12-fold, respectively).…”

Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation

“… 114 PGAM5 is a mitochondrial serine/threonine phosphatase that is upregulated in HCC tissue. 121 PGAM5 interacts with anti-apoptotic protein Bcl-XL, thereby preventing its degradation and inhibiting apoptosis. 121 Additionally, increased MCUR1 expression was associated with increased expression of anti-apoptotic protein Bcl-2.…”

Mitochondrial Quality Control in Hepatocellular Carcinoma

“…Resistance to apoptosis also plays a role in the chemoresistance mechanisms of liver cancer cells. For example, an increased expression of mitochondrial phosphoglycerate mutase/protein phosphatase in liver cancer cells enhances chemoresistance to 5-fluorouracil by increasing the stability of Bcl-XL, and inhibiting the expression of Bax and cytochrome c, which eventually inhibit the apoptotic signaling pathway ( 29 ). A study suggested that HCC can resist apoptosis by overexpressing mitochondrial uncoupling protein to decrease mitochondrial membranes permeability ( 30 ).…”