Crucial Role of Heme Oxygenase-1 on the Sensitivity of Cholangiocarcinoma Cells to Chemotherapeutic Agents

Abstract

Cancer cells acquire drug resistance via various mechanisms including enhanced cellular cytoprotective and antioxidant activities. Heme oxygenase-1 (HO-1) is a key enzyme exerting potent cytoprotection, cell proliferation and drug resistance. We aimed to investigate roles of HO-1 in human cholangiocarcinoma (CCA) cells for cytoprotection against chemotherapeutic agents. KKU-100 and KKU-M214 CCA cell lines with high and low HO-1 expression levels, respectively, were used to evaluate the sensitivity to chemotherapeutic agents, gemcitabine (Gem) and doxorubicin. Inhibition of HO-1 by zinc protoporphyrin IX (ZnPP) sensitized both cell types to the cytotoxicity of chemotherapeutic agents. HO-1 gene silencing by siRNA validated the cytoprotective effect of HO-1 on CCA cells against Gem. Induction of HO-1 protein expression by stannous chloride enhanced the cytoprotection and suppression of apoptosis caused by anticancer agents. The sensitizing effect of ZnPP was associated with increased ROS formation and loss of mitochondrial transmembrane potential, while Gem alone did not show any effects. A ROS scavenger, Tempol, abolished the sensitizing effect of ZnPP on Gem. Combination of ZnPP and Gem enhanced the release of cytochrome c and increased p21 levels. The results show that HO-1 played a critical role in cytoprotection in CCA cells against chemotherapeutic agents. Targeted inhibition of HO-1 may be a strategy to overcome drug resistance in chemotherapy of bile duct cancer.

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

“…We have recently shown that activation of the Ras-Raf-ERK pathway promotes overexpression of HO-1 and survival of renal cancer cells (13). Induction of HO-1 in cancer is often associated with resistance of cancer cells to chemotherapeutic drugs (6,37,38); and inhibition of HO-1 in combination with chemotherapy can be a possible and effective therapeutic strategy to enhance efficiency of cancer treatment (8,10,14). In this study, we demonstrate that knockdown of HO-1 significantly augments RAPA-and sorafenib-induced apoptosis of renal cancer cells.…”

“…HO-1 is overexpressed in different types of cancers and is further induced by radiation and chemotherapy (6,10,11). HO-1 endorses survival of various cancers, including hepatoma, melanoma, thyroid and lung carcinoma, while inhibition of HO-1 reduces viability of colon carcinoma, acute myeloid leukemia and induces apoptosis of renal cancer cells (12,13).…”

“…HO-1 endorses survival of various cancers, including hepatoma, melanoma, thyroid and lung carcinoma, while inhibition of HO-1 reduces viability of colon carcinoma, acute myeloid leukemia and induces apoptosis of renal cancer cells (12,13). The protective function of HO-1 thus turns out to be a double-edged sword, as cancer cells utilize the anti-apoptotic effects of HO-1 as a shield from che-motherapeutic drugs (6,10,14). However, there are few reports about anti-proliferative role of HO-1 in prostate and breast cancer (15,16).…”

Proapoptotic effects of heme oxygenase-1 inhibitor on Kasumi-1 cells via the ATF4/CHOP/Ire-1α pathway

“…HO-1 is the most interesting protein in terms of protecting different types of tumor cells from apoptosis, promoting their proliferation, and enhancing their invasion (Castilho et al, 2012;Kongpetch et al, 2012;Zhang et al, 2013;Furfaro et al, 2014). We previously reported that induction of HO-1 expression facilitated the growth of chronic myelocytic leukemia cells, whereas inhibition promoted their apoptosis (Chen et al, 2012;Wang et al, 2012).…”

Dysregulated Expression of MITF in Subsets of Hepatocellular Carcinoma and Cholangiocarcinoma

“…3B). We also analyzed expression levels of HO-1 that is an enzyme responsible for physiological heme catabolism (Shibahara 2003) and also plays a cytoprotective role in cholangiocarcinoma cells (Kongpetch et al 2012). GANT61 at 10 or 20 µM induced the expression of HO-1 in HepG2 cells, HuCCT1 cells, and KKU-100 cells, which may contribute to the survival of these cancer cells.…”