Heat Shock Proteins HSPA1 and HSP90AA1 Are Upregulated in Colorectal Polyps and Can Be Targeted in Cancer Cells by Anti-Inflammatory Oxicams with Arylpiperazine Pharmacophore and Benzoyl Moiety Substitutions at Thiazine Ring

Abstract

Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp malignancy potential and examined the effect of piroxicam, meloxicam and five novel analogues on HSPA1 and HSP90AA1 expression (mRNA/protein) in colorectal adenocarcinoma lines. HSPA1 and HSP90AA1 were upregulated in polyps by 3- and 2.9-fold. Expression ratios were higher in polyps with higher dysplasia grade and dominant villous growth pattern, mostly a result of diminished gene expression in normal tissue. Classic oxicams had negligible/non-significant effect on HSP expression. Their most effective analogue inhibited HSPA1 protein and gene by 2.5-fold and 5.7-fold in Caco-2 and by 11.5-fold and 6.8-fold in HCT116 and HSPA1 protein in HT-29 by 1.9-fold. It downregulated HSP90AA1 protein and gene by 1.9-fold and 3.7-fold in Caco-2 and by 2-fold and 5.0-fold in HCT116. HSPA1 and HSP90AA1 are upregulated in colorectal polyps reflecting their potential for malignancy. HSPA1 in cancer cells and, to lesser degree, HSP90AA1 can be reduced by oxicam analogues with thiazine ring substituted via propylene linker by arylpiperazine pharmacophore with fluorine substituents and by benzoyl moiety.

Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer

“…They downregulate redox-sensitive and inflammation-associated transcription-factors NF-κB and AP-1, and reduce their DNA-binding capacity [ 21 ]. The NSAIDs have also been demonstrated to downregulate the expression of heat shock proteins [ 22 ], known regulators of cellular-redox status [ 23 ] and chemokine chaperones ( Figure 1 ). The oxicam protagonist, piroxicam, reduces the incidence and the size of tumors in animal models of CRC [ 11 , 12 ].…”

Agarose/crystalline nanocellulose (CNC) composites promote bone marrow-derived mast cell integrity, degranulation and receptor expression but inhibit production of de novo synthesized mediators

“…BMMC cultured on CNC/agarose upregulated 7 genes that were effectively absent in cells that were cultured on agarose alone. These genes include heat shock proteins Hspa1a and Hspa1b which serve as chaperones for other proteins involved in cytoskeleton function and have been associated with atrial fibrillation and colorectal polyp formation ( Szczuka et al, 2021 ; van Marion et al, 2021 ). These proteins appear to be essential in cellular responses to changes in microenvironment and therefore it is unsurprising that their expression is induced in BMMC cultured on CNC/agarose.…”

Establishment of a Necroptosis-Related Prognostic Signature to Reveal Immune Infiltration and Predict Drug Sensitivity in Hepatocellular Carcinoma

“…Studies found that 25% of patients with neuroblastoma showed an MYCN amplification and predicted poor prognosis independently of other factors ( Brodeur et al, 1984 ; Seeger et al, 1985 ). HSP90AA1 , one of the HSP90 isoforms, showed a significant correlation with survival time in lung cancer patients by inhibiting the AKT1 and ERK pathways ( Niu et al, 2021 ) and was upregulated in colorectal cancer ( Szczuka et al, 2021 ). HSP90 regulates the stability of MLKL and RIP3 and is required for TNF-stimulated necrosome assembly ( Zhao et al, 2016 ).…”