Q6, a novel hypoxia-targeted drug, regulates hypoxia-inducible factor signaling via an autophagy-dependent mechanism in hepatocellular carcinoma

Abstract

Tumor hypoxia underlies treatment failure and yields more aggressive and metastatic cancer phenotypes. Although therapeutically targeting these hypoxic environments has been proposed for many years, to date no approaches have shown the therapeutic value to gain regulatory approval. Here, we demonstrated that a novel hypoxia-activated prodrug, Q6, exhibits potent antiproliferative efficacy under hypoxic conditions and induces caspase-dependent apoptosis in 2 hepatocellular carcinoma (HCC) cell lines, with no obvious toxicity being detected in 2 normal liver cell lines. Treatment with Q6 markedly downregulated HIF1A [hypoxia inducible factor 1, α subunit (basic helix-loop-helix transcription factor)] expression and transcription of the downstream target gene, VEGFA (vascular endothelial growth factor A). This dual hypoxia-targeted modulation mechanism leads to high potency in suppressing tumor growth and vascularization in 2 in vivo models. Intriguingly, it is the autophagy-dependent degradation pathway that plays a crucial role in Q6-induced attenuation of HIF1A expression, rather than the proteasome-dependent pathway, which is normally regarded as the predominant mechanism underlying posttranslational regulation of HIF1A. Inhibition of autophagy, either by short interfering RNA (siRNA) or by chemical inhibitors, blocked Q6-induced HIF1A degradation. Autophagic degradation of HIF1A was further confirmed by the observation that HIF1A coimmunoprecipitated with the ubiquitin-binding adaptor protein, SQSTM1, which is degraded through autophagy. Additionally, silencing of SQSTM1 inhibited Q6-induced HIF1A degradation. These findings suggest that the novel hypoxia-targeted agent, Q6, has potential clinical value in the therapy of HCC. Furthermore, the identification of autophagy as a crucial regulator of HIF1A provides new insights into hypoxia-related treatments.

Hypoxia promotes bone marrow-derived mesenchymal stem cell proliferation through apelin/APJ/autophagy pathway

“…Autophagy plays an important role in the process of hypoxia. Recent studies have indicated that HIF-1 regulates the autophagy under hypoxia [20]. On the contrary, it was reported that oxygen deprivationinduced autophagy does not require HIF-1 activity.…”

Pheochromocytoma: Gasping for Air

“…Nowadays, several agents affecting HIF-1α signaling have been introduced, with varying results depending on a cancer's HIF-α phenotype [43, [186][187][188]. They include antiangiogenic agents, such as inhibitors of vascular endothelial growth factor (VEGF), mTOR, and heat shock protein 90 inhibitors, or agents that restore or activate PHD enzyme activity.…”

Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells

“…Chemo-therapy has been used for over 30 years but resistance remains a significant barrier for both cytotoxic and targeted agents, and therefore has triggered great research efforts worldwide for new treatment modalities that might be applicable to this cancer [4,5]. Due to hypovascularity, the hepatic tumors are significantly more hypoxic than adjacent normal tissues (ANT) [6,7]. To adapt to this unfavorable condition, cancer cells would activate various biological behaviors, such as angiogenesis, and migration to less hypoxic and more nutritious areas [8][9][10].…”