Heme Oxygenase-1 Promotes Survival of Renal Cancer Cells through Modulation of Apoptosis- and Autophagy-regulating Molecules

2012/07/27 by Pallavi Banerjee, Aninda Basu, Barbara Wegiel +7 · 25 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Heme Oxygenase-1 and Carbon Monoxide #Autophagy in Disease and Therapy #Cannabis and Cannabinoid Research

paper · pdf · doi:10.1074/jbc.m112.393140

Abstract

The cytoprotective enzyme heme oxygenase-1 (HO-1) is often overexpressed in different types of cancers and promotes cancer progression. We have recently shown that the Ras-Raf-ERK pathway induces HO-1 to promote survival of renal cancer cells. Here, we examined the possible mechanisms underlying HO-1-mediated cell survival. Considering the growing evidence about the significance of apoptosis and autophagy in cancer, we tried to investigate how HO-1 controls these events to regulate survival of cancer cells. Rapamycin (RAPA) and sorafenib, two commonly used drugs for renal cancer treatment, were found to induce HO-1 expression in renal cancer cells Caki-1 and 786-O; and the apoptotic effect of these drugs was markedly enhanced upon HO-1 knockdown. Overexpression of HO-1 protected the cells from RAPA- and sorafenib-induced apoptosis and also averted drug-mediated inhibition of cell proliferation. HO-1 induced the expression of anti-apoptotic Bcl-xL and decreased the expression of autophagic proteins Beclin-1 and LC3B-II; while knockdown of HO-1 down-regulated Bcl-xL and markedly increased LC3B-II. Moreover, HO-1 promoted the association of Beclin-1 with Bcl-xL and Rubicon, a novel negative regulator of autophagy. Drug-induced dissociation of Beclin-1 from Rubicon and the induction of autophagy were also inhibited by HO-1. Together, our data signify that HO-1 is up-regulated in renal cancer cells as a survival strategy against chemotherapeutic drugs and promotes growth of tumor cells by inhibiting both apoptosis and autophagy. Thus, application of chemotherapeutic drugs along with HO-1 inhibitor may elevate therapeutic efficiency by reducing the cytoprotective effects of HO-1 and by simultaneous induction of both apoptosis and autophagy. The cytoprotective enzyme heme oxygenase-1 (HO-1) is often overexpressed in different types of cancers and promotes cancer progression. We have recently shown that the Ras-Raf-ERK pathway induces HO-1 to promote survival of renal cancer cells. Here, we examined the possible mechanisms underlying HO-1-mediated cell survival. Considering the growing evidence about the significance of apoptosis and autophagy in cancer, we tried to investigate how HO-1 controls these events to regulate survival of cancer cells. Rapamycin (RAPA) and sorafenib, two commonly used drugs for renal cancer treatment, were found to induce HO-1 expression in renal cancer cells Caki-1 and 786-O; and the apoptotic effect of these drugs was markedly enhanced upon HO-1 knockdown. Overexpression of HO-1 protected the cells from RAPA- and sorafenib-induced apoptosis and also averted drug-mediated inhibition of cell proliferation. HO-1 induced the expression of anti-apoptotic Bcl-xL and decreased the expression of autophagic proteins Beclin-1 and LC3B-II; while knockdown of HO-1 down-regulated Bcl-xL and markedly increased LC3B-II. Moreover, HO-1 promoted the association of Beclin-1 with Bcl-xL and Rubicon, a novel negative regulator of autophagy. Drug-induced dissociation of Beclin-1 from Rubicon and the induction of autophagy were also inhibited by HO-1. Together, our data signify that HO-1 is up-regulated in renal cancer cells as a survival strategy against chemotherapeutic drugs and promotes growth of tumor cells by inhibiting both apoptosis and autophagy. Thus, application of chemotherapeutic drugs along with HO-1 inhibitor may elevate therapeutic efficiency by reducing the cytoprotective effects of HO-1 and by simultaneous induction of both apoptosis and autophagy.

Cited by

• The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways. [europepmc]
• Functional microRNA library screening identifies the hypoxamir miR-24 as a potent regulator of smooth muscle cell proliferation and vascularization. [europepmc]
• Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. [europepmc]
• Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients. [europepmc]
• Heme oxygenase-1 and acute kidney injury. [europepmc]
• Expression of methionine adenosyltransferase 2A in renal cell carcinomas and potential mechanism for kidney carcinogenesis. [europepmc]
• Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species. [europepmc]
• CYLD-mediated signaling and diseases. [europepmc]
• ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. [europepmc]
• Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells. [europepmc]
• Autophagy and Tubular Cell Death in the Kidney. [europepmc]
• Pathological significance and prognostic implications of heme oxygenase 1 expression in non-muscle-invasive bladder cancer: Correlation with cell proliferation, angiogenesis, lymphangiogenesis and expression of VEGFs and COX-2. [europepmc]
• Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury. [europepmc]
• Honokiol inhibits c-Met-HO-1 tumor-promoting pathway and its cross-talk with calcineurin inhibitor-mediated renal cancer growth. [europepmc]
• Adipocyte-activated oxidative and ER stress pathways promote tumor survival in bone via upregulation of Heme Oxygenase 1 and Survivin. [europepmc]
• A Dual Role of Heme Oxygenase-1 in Cancer Cells. [europepmc]
• Nrf2-Heme oxygenase-1 modulates autophagy and inhibits apoptosis triggered by elevated glucose levels in renal tubule cells. [europepmc]
• Heme Oxygenase-1 Inhibition Sensitizes Human Prostate Cancer Cells towards Glucose Deprivation and Metformin-Mediated Cell Death. [europepmc]
• Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels. [europepmc]
• Oxidized Lipoproteins Promote Resistance to Cancer Immunotherapy Independent of Patient Obesity. [europepmc]
• The dual role and mutual dependence of heme/HO-1/Bach1 axis in the carcinogenic and anti-carcinogenic intersection. [europepmc]
• Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer. [europepmc]
• Cytoprotective Role of Heme Oxygenase-1 in Cancer Chemoresistance: Focus on Antioxidant, Antiapoptotic, and Pro-Autophagy Properties. [europepmc]
• CYLD in health and disease. [europepmc]
• A novel combination therapy with Cabozantinib and Honokiol effectively inhibits c-Met-Nrf2-induced renal tumor growth through increased oxidative stress. [europepmc]

Related

• ROS in cancer therapy: the bright side of the moon
• Reactive Oxygen Species (ROS): Key Components in Cancer Therapies
• Hypoxia-inducible factor-2α regulates the expression of TRAIL receptor DR5 in renal cancer cells
• Pro-survival autophagy: An emerging candidate of tumor progression through maintaining hallmarks of cancer
• The Dual Role of Autophagy in Cancer: Mechanisms and Therapeutic Strategies