Sorafenib-Mediated Targeting of the AAA+ ATPase p97/VCP Leads to Disruption of the Secretory Pathway, Endoplasmic Reticulum Stress, and Hepatocellular Cancer Cell Death

Abstract

The molecular mechanisms and cellular targets of sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC), remain to be fully characterized. Recent studies have shown that sorafenib induces tumor cell death through the activation of endoplasmic reticulum stress signaling and/or autophagy in various cellular models. Using liver cancer-derived cell lines, we specifically show that the IRE1 and phosphorylated extracellular signal-regulated kinase arms of the unfolded protein response (UPR) become activated upon sorafenib treatment, whereas the ATF6 arm is inhibited. Our results also reveal that sorafenib treatment causes disruption to the secretory pathway, as witnessed by the fragmentation of the Golgi apparatus and the induction of autophagy. On the basis of these observations, we tested the relevance of the AAA þ ATPase p97/VCP as a potential functional target of sorafenib. Our results show that p97/VCP tyrosine phosphorylation is prevented upon sorafenib treatment, and that this can be correlated with enhanced membrane association. Moreover, we show that DBeQ, a recently discovered inhibitor of p97/VCP, enhances sorafenib-mediated toxicity in cultured cells. Our data show a novel mechanism for sorafenib-mediated cell death in HCC, which depends on the integrity of the secretory pathway; and we identify p97/VCP phosphorylation as a potential target for improved sorafenib treatment efficacy in patients.

miR-339-5p inhibits cell migration and invasion in vitro and may be associated with the tumor-node-metastasis staging and lymph node metastasis of non-small cell lung cancer

“…Studies have shown that the expression levels of VCP correlate with the prognosis and recurrence of specific human cancers, including hepatocellular, gastric and colorectal carcinomas. In these studies, VCP expression was found to correlate with the prognosis of differentiated thyroid carcinoma (26–28). It is speculated that miR-339-5p inhibits the VCP expression to inhibit the metastasis of lung cancer, but the exact mechanism is unclear.…”

Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy

“…These are described in more detail below. In addition a number of other inhibitors have been reported, including Eer1 [104] (Figure 6A), 2-anilino-4-aryl-1,3-thiazoles (Figure 6B,C) [105,106], xanthohumol [107] (Figure 6E), the tyrosine kinase inhibitor sorafenib [108] (Figure 6F), the covalent inhibitor NMS859 [99] (Figure 6I), KUS69 [109] (the most potent of five closely related KUS compounds), rheoemodin (Figure 6L), 1-hydroxydehydroherbarin (Figure 6M), phomapyrrolidone A [110] (Figure 6N), and Syk inhibitor III [111].

Figure 6 Structures of p97 inhibitors.

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High expression of valosin-containing protein predicts poor prognosis in patients with breast carcinoma

“…VCP is associated with various cellular pathology types and disease states, including pulmonary conditions, neurodegenerative disorders, and other disorders linked with protein misfolding [4][5][6]. Multiple studies have reported a high correlation between elevated expression of VCP and progression, prognosis, and metastatic potential in pancreatic cancer, esophageal carcinoma, colorectal carcinoma, liver cancer, and prostate cancer [7][8][9][10][11].…”