Targeting of distinct signaling cascades and cancer-associated fibroblasts define the efficacy of Sorafenib against prostate cancer cells

Abstract

Sorafenib, a multi-tyrosine kinase inhibitor, kills more effectively the non-metastatic prostate cancer cell line 22Rv1 than the highly metastatic prostate cancer cell line PC3. In 22Rv1 cells, constitutively active STAT3 and ERK are targeted by sorafenib, contrasting with PC3 cells, in which these kinases are not active. Notably, overexpression of a constitutively active MEK construct in 22Rv1 cells stimulates the sustained phosphorylation of Bad and protects from sorafenib-induced cell death. In PC3 cells, Src and AKT are constitutively activated and targeted by sorafenib, leading to an increase in Bim protein levels. Overexpression of constitutively active AKT or knockdown of Bim protects PC3 cells from sorafenib-induced killing. In both PC3 and 22Rv1 cells, Mcl-1 depletion is required for the induction of cell death by sorafenib as transient overexpression of Mcl-1 is protective. Interestingly, co-culturing of primary cancer-associated fibroblasts (CAFs) with 22Rv1 or PC3 cells protected the cancer cells from sorafenib-induced cell death, and this protection was largely overcome by co-administration of the Bcl-2 antagonist, ABT737. In summary, the differential tyrosine kinase profile of prostate cancer cells defines the cytotoxic efficacy of sorafenib and this profile is modulated by CAFs to promote resistance. The combination of sorafenib with Bcl-2 antagonists, such as ABT737, may constitute a promising therapeutic strategy against prostate cancer.

Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15

“…High GDF15 expression in both stroma and epithelium was the most abundant staining pattern of the cases analyzed. Subsequent analysis of primary human prostate CAFs, established in our laboratory (34), confirmed that fibroblasts express GDF15 as proposed by the in situ staining (Fig. 1D).…”

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

“…nih.gov/pubmed). Among the clinical studies testing the safety and efficacy of ICD-inducing chemotherapeutics employed as off-label indications, we would like to highlight the works of: (1) Butts and collaborators (Cross Cancer Institute; Edmonton, Canada), who reported that the therapeutic activity of a tumortargeting vaccine administered to non-small cell lung carcinoma (NSCLC) patients previously receiving cyclophosphamide-based chemotherapy may be influenced by the administration schedule (i.e., sequential vs. concurrent) of the latter; 84 (2) Roulstone and colleagues (The Institute of Cancer Research; London, UK), who demonstrated that the pre-administration of high-dose cyclophosphamide to individuals with solid tumors is unable to prevent the development of humoral, neutralizing immunity against oncolytic reoviruses; 85 (3) Bazzola and co-authors (Azienda Istituti Ospitalieri di Cremona; Cremona, Italy), who tested metronic cyclophosphamide combined with letrezole (a nonsteroidal aromatase inhibitor) and sorafenib (a multi-targeted kinase inhibitor) 86,87 in primary breast cancer patients, with promising results; 88 , who provided evidence in support of the therapeutic activity of oxaliplatin as part of neoadjuvant chemotherapeutic regimens for patients with refractory or chemotherapy-na€ ıve pancreatic carcinoma; 97,98 (9) Straus and coauthors (Memorial Sloan-Kettering Cancer Center, New York, NY, US), who reported that the administration of liposomal doxorubicin to subjects with cutaneous T-cell lymphoma is associated with an objective responses rate that is among the highest ever reported for similar patient cohorts, while the subsequent application of bexarotene (a retinoid) [99][100][101][102] has negligible effects on response rate and duration. 103 Preclinical and translational advances.…”

Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells

“…It is notable that we were unable to detect STAT3 phosphorylation in PC3 cells, despite detectable levels of STAT3 protein. Indeed, conflicting findings regarding STAT3 phosphorylation and locus deletion in PC3 cells have been reported in the literature (53)(54)(55)(56)(57). Nevertheless, total and partial STAT3 knockdown significantly decreased PC3 cell proliferation, a finding inconsistent with the phenotype of IL-11 knockdown cells, yet suggesting that STAT3 does play an impor-tant oncogenic role in PC3 cells (data not shown).…”