Heme oxygenase-1 inhibition mediates Gas6 to enhance bortezomib-sensitivity in multiple myeloma via ERK/STAT3 axis

Abstract

Chemoresistance is still a critical challenge for efficient treatment of multiple myeloma (MM) during the bortezomib-based chemotherapy. Recent studies have suggested that heme oxygenase-1 (HO-1) is involved in apoptosis, proliferation and chemoresistance in cancer cells. Here we aim to investigate the role and mechanism of HO-1 in bortezomib-sensitivity to myeloma cells. In the study population, we found that HO-1 was highly expressed in CD138 + primary myeloma cells, which was positively associated with Gas6 expression and Gas6 plasma levels in MM patients. Downregulation of HO-1 using pharmacological inhibitor ZnPPIX or siRNA knockdown significantly enhanced myeloma cell sensitivity to bortezomib in human primary CD138 + cells, U266 and RPMI8226 cell lines. Mechanistically, HO-1 regulated Gas6 production via ERK/STAT3 axis. Combination with HO-1 inhibition increased bortezomib-induced apoptosis and antiproliferative effects via suppressing Gas6 production. These findings suggest that combination of bortezomib and HO-1 inhibitor may serve as a promising therapeutic target against bortezomib-resistant MM. www.aging-us.com 6612 AGING with chemoresistance [13]. However, the underlying mechanisms between HO-1 and chemoresistance remain unclear. Growth arrest-specific gene 6 (Gas6) is a 75 kDa secreted protein containing an N-terminal gamma-carboxyglutamic acid domain [14]. Gas6 has been implicated in promoting proliferation, migration and survival of multiple types of cancer cells, including breast, melanoma, ovarian, renal and prostate cancers [15-19]. Besides, emerging evidence indicate that high expression of Gas6 is associated with a poor prognosis in hematologic malignancies. Patients with acute myeloid leukemia expressing Gas6, especially those aged ≥60 years, more often fail to achieve a complete remission and have shorter disease-free and overall survive than those without Gas6 expression [20]. In addition, aberrant Gas6 secretion promotes acute myeloid leukemia cells growth and chemoresistance [21]. It suggests that Gas6 represents a critical factor for chemoresistance. However, whether HO-1 mediates the sensitivity of MM to bortezomib via Gas6 is still unknown and remains to be investigated. We hypothesized that HO-1 inhibition downregulates Gas6 to overcome adaptive bortezomib resistance in MM, providing a potential target against drug resistance in the treatment of MM. Additionally, we aimed at investigating the molecular mechanism how HO-1 regulates Gas6 in bortezomib-resistant myeloma cells. RESULTS High HO-1 expression is associated with increased Gas6 expression in patients with MM

STAT3 Pathway in Gastric Cancer: Signaling, Therapeutic Targeting and Future Prospects

“…Brevilin A suppresses the phosphorylation of STAT3 at tyrosine 70 to restrict the growth of lung cancer cells [55]. These studies are in line with the fact that STAT3 is a tumorigenesis factor in cancer cells, and its inhibition is an ideal strategy in overcoming cancer (Table 1) [56][57][58][59]. it was translated into clinical trials.…”

“…Briefly, miRs are endogenous non-coding RNA with a low length of 19-23 nucleotides and can affect various biological processes via targeting different molecular pathways [84][85][86][87][88][89]. A high number of studies have demonstrated that miRs are able to regulate the STAT3 signaling pathway by targeting upstream mediators, such as ROCK1 [59], suppressing translation and phosphorylation [90], affecting JAK proteins [91] and influencing the nuclear translocation of STAT3 [92]. A similar phenomenon occurs in GC cells.…”

Hypoxia‐induced oxidative stress promotes therapy resistance via upregulation of heme oxygenase‐1 in multiple myeloma

“…34 It has also been reported that HMOX1 induces bortezomib resistance by inhibiting the APRIL-NF-κB-CCL3 signaling pathways and interfering with the ERK-STAT3-Gas6 axis. 35,36 These reports suggest that HMOX1 could affect the antimyeloma effect of bortezomib in a negative feedback manner. However, although HMOX1 expression is induced by hypoxia, the critical function of HMOX1 in myeloma cells adapted to a hypoxic microenvironment remains unclear.…”

Immune Modulation by Inhibitors of the HO System

“…As it was mentioned above, the expression of HO was shown to increase after chemo- and radiotherapy, which could contribute to decreasing treatment effectiveness [ 105 ]. Accordingly, the aggressive phenotype of rhabdomyosarcoma was shown to be reduced by treatment with HO-1 inhibitors [ 106 ], and other studies suggested that the use of ZnPP can increase the sensitivity and susceptibility to chemotherapy of hepatoma cells [ 39 ] and ex vivo samples obtained from multiple myeloma patients [ 107 ]. Moreover, ZnPP treatment reduces tumor growth and liver metastasis in a mouse model for neuroblastoma [ 108 ].…”

“…Furthermore, HO expression is related to the immunosuppressive function of dendritic cells and dysfunction of T cells [ 110 , 111 ]; thus, HO inhibition by shRNA or ZnPP improves dendritic cells maturation and revokes the unresponsiveness of CD4 and CD8 T-effector cells in neuroblastoma, glioma cells, and multiple myeloma [ 107 , 108 , 110 ].…”