Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance

Abstract

Although docetaxel (DOX) is the standard of care for advanced prostate cancer (PCa), most patients develop resistance to DOX. Therefore, elucidating the mechanism that underlies resistance to DOX is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 PCa cell line and its DOX-resistant derivative (PC3-TxR) revealed decreased latexin (LXN) expression in the resistant cells. LXN expression was inversely correlated with taxane resistance in a panel of PCa cell lines. LXN knockdown conferred DOX resistance to PCa cells in vitro and in vivo; whereas LXN overexpression reduced DOX resistance in several PCa cell lines. A mouse model of PCa demonstrated that PCa cells developed resistance to DOX in the bone microenvironment, but not the soft tissue microenvironment. This was associated with decreased LXN expression in PCa cells in the bone microenvironment compared to the soft tissue microenvironment. It was identified that bone stromal cells decreased LXN expression through methylation and induced chemoresistance in PCa in vitro. These findings reveal that a subset of PCa develops DOX resistance through loss of LXN expression associated with methylation and that the bone microenvironment promotes this drug resistance phenotype.

The Intersection between Oral Microbiota, Host Gene Methylation and Patient Outcomes in Head and Neck Squamous Cell Carcinoma

“…Associations of lower tumor stage and improved cancer-specific survival with enrichment of F. nucleatum in HNSCC cases were also novel observations. The finding of better clinical outcomes associated with elevated levels of F. nucleatum in HNSCC when comparing tumor with adjacent normal tissue is, however, in contrast to poorer survival and worse prognosis of F. nucleatum infection in colorectal cancer (CRC) [ 37 , 38 , 39 ] and esophageal cancer [ 40 ]. Long-term smoking, alcohol consumption, and high-risk human papillomavirus (HPV) infection are established oncogenic drivers in HNSCC [ 41 ].…”

“…Interestingly, an integrative analysis identified that the enrichment of F. nucleatum was associated with host gene promoter methylation, which further implies its pathophysiologic role in regulating transcriptome level involvement in pro-inflammatory and cell proliferation processes [ 9 , 10 ]. The tumor suppressor gene (TSG) latexin ( LXN ) has been downregulated in a number of human cancers, including lymphoma, gastric carcinoma, and thyroid carcinoma [ 37 , 38 , 39 ], and the TCGA HNSCC cohort, in congruence with its promoter hypermethylation in Fusobcaterium -high tumor tissues. LXN has also been shown to be involved in the inflammatory response with inhibition of tumor growth and colony formation [ 40 , 42 ].…”

Infiltrating CD4+ T cells attenuate chemotherapy sensitivity in prostate cancer via CCL5 signaling

“…Doc‐based treatment is the first‐line chemotherapy for metastatic CRPC since 2004; however, chemoresistance remains a big challenge for the current PCa therapy . Especially the mechanism of resistance to Doc is poorly understood.…”

“…While CRPC is generally a Doc‐sensitive disease, there is a large variability in its response because of inherent or acquired Doc resistance. Approximately half of all patients do not respond to Doc and those who do eventually develop resistance to Doc within 24 months of initial exposure …”

Establishment and characterization of two cabazitaxel-resistant prostate cancer cell lines

“…In contrast, overexpression of P-gp did not contribute to paclitaxel-resistance in PC-3-TxR cells although it was observed. Repression of C-terminal tensin like protein (CTEN) expression and inhibition of latexin expression appear to be some mechanisms through which PC-3-TxR cells became paclitaxel-resistant [ 21 ] [ 22 ]. Therefore, we speculated that different mechanisms might promote cabazitaxel-resistance in PC-3-TxR versus DU145-TxR cells.…”