title: Heme oxygenase-1 promotes survival of renal cancer cells through modulation of apoptosis- and autophagy-regulating molecules.
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.
authors: Division of Nephrology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors: Pallavi
authors: P
authors: Banerjee
authors: Aninda
authors: A
authors: Basu
authors: Barbara
authors: B
authors: Wegiel
authors: Leo E
authors: LE
authors: Otterbein
authors: Kenji
authors: K
authors: Mizumura
authors: Martin
authors: M
authors: Gasser
authors: Ana Maria
authors: AM
authors: Waaga-Gasser
authors: Augustine M
authors: AM
authors: Choi
authors: Soumitro
authors: S
authors: Pal
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D001557:Benzenesulfonates / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011524:Protoporphyrins / Q000737:chemistry; D011725:Pyridines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D000077157:Sorafenib
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D001557:Benzenesulfonates; D047908:Intracellular Signaling Peptides and Proteins; C502070:MAP1LC3B protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D010671:Phenylurea Compounds; D011524:Protoporphyrins; D011725:Pyridines; C552537:RUBCN protein, human; D009536:Niacinamide; D000077157:Sorafenib; D051547:Heme Oxygenase-1; D020123:Sirolimus