Abstract 2272: Heme oxygenase-1 regulates apoptosis and autophagy for the survival of renal cancer cells
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation pathway is classically known for its cytoprotective role during tissue injury. However, this protective function of HO-1, which is essential for maintaining cellular homeostasis under stress conditions, may act as a double-edged sword by promoting survival of cancer cells. HO-1 is overexpressed in different cancers, and cancer cells may utilize the anti-apoptotic effects of HO-1 as a shield against chemotherapeutic agents. We have recently demonstrated that activation of the oncogenic Ras pathway induces HO-1 to promote survival of renal cancer cells. Recent studies show that along with apoptosis, type II cell death or autophagy also plays a vital role in regulating the fate of cancer cells. While some groups suggest that toxic autophagy cooperates with chemotherapeutic agents to facilitate apoptosis of cancer cells, others propose a protective role of autophagy in cancer. Here, we investigated whether HO-1 can control apoptosis- and autophagy-related genes to regulate survival of human renal cancer cells (786-0 and Caki-1). We overexpressed HO-1 in these cells either by CoPP treatment, a known inducer of HO-1, or by transfecting the cells with a human HO-1 overexpression plasmid. We observed that the overexpression of HO-1 increased the level of anti-apoptotic protein Bcl-xL as observed by Western blot analysis; and this was associated with a significant decrease in the expression of autophagic proteins Beclin-1 and LC3B-II. The knockdown of HO-1 using specific siRNA led to down-regulation of Bcl-xL, and a marked increase in LC3B-II expression. Moreover, we found that the treatment of renal cancer cells with either rapamycin or sorafenib (two commonly used drugs for the treatment of renal cancer) induced the protein expression of HO-1; and apoptotic effects of these drugs on cancer cells were markedly enhanced in presence of the HO-1 inhibitor SnPP as observed by FACS analysis using Annexin-V staining. Together, our results indicate that HO-1 is up-regulated in renal cancer cells for their survival against chemotherapeutic agents, and it may protect the cells from both apoptosis- and autophagy-mediated death. Besides, recent studies demonstrated that both rapamycin and sorafenib can induce autophagy. Considering this together with our data, we suggest that application of these drugs along with HO-1 inhibitor may result in more efficient killing of renal cancer cells by reducing cytoprotective effects of HO-1 and by simultaneous induction of both autophagy and apoptosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2272. doi:1538-7445.AM2012-2272