Plecstatin-1 induces an immunogenic cell death signature in colorectal tumour spheroids

Abstract

Treatment with plecstatin-1 resulted in disruption of the cytoskeleton and phosphorylation of the stress marker eIF2α, and induction of an immunogenic cell death signature, including calreticulin, high mobility group protein B and extracellular ATP.

Plectin in Cancer: From Biomarker to Therapeutic Target

“…Indeed, an exploration into the function of the plectin mislocalized to the cell surface has demonstrated a role in many tumor processes, including cell cycle, migration, and immune escape, pointing to the potential of anti-CSP antibody therapy [16,25,26,98]. As presented in a companion research article in this Cells Special Issue, the investigation into the effects of a novel anti-CSP antibody in ovarian cancer revealed a dramatic decrease in tumor growth in ovarian cancer murine models and unraveled a wealth of anti-tumor mechanisms associated with anti-CSP treatment [98].…”

“…Given that an impaired immune system is a hallmark of solid tumors, there is great interest in identifying key regulators to inform appropriate therapeutic strategies [ 91 ]. Strikingly, the selective inhibition of plectin and CSP with a metallodrug, plecstatin-1, induced an in vitro immunogenic cell death signature [ 25 ]. Blocking plectin and CSP resulted in the secretion of ATP, the release of high mobility group box-1 (HMGB-1), and increased translocation of danger-associated molecular patterns (DAMPs) such as calreticulin, HSP90, and HSP70 to the plasma membrane [ 25 ].…”

“…Strikingly, the selective inhibition of plectin and CSP with a metallodrug, plecstatin-1, induced an in vitro immunogenic cell death signature [ 25 ]. Blocking plectin and CSP resulted in the secretion of ATP, the release of high mobility group box-1 (HMGB-1), and increased translocation of danger-associated molecular patterns (DAMPs) such as calreticulin, HSP90, and HSP70 to the plasma membrane [ 25 ]. Although additional studies are required to evaluate plectin’s immunogenic role in vivo, this report demonstrates that inhibition of plectin could have immunogenic consequences.…”

“…However, the adverse side effects and the emergence of drug resistance limit the use of platinum first-line cancer drugs such as cisplatin, carboplatin, and oxaliplatin [ 125 ]. Alternatively, plecstatin-1, an organoruthenium drug candidate that selectively targets plectin and CSP, has been identified as a promising anti-cancer strategy [ 25 , 26 , 27 ]. In colon cancer cells (HCT116), administration of plecstatin-1 induced G0/G1 arrest [ 26 ].…”

“…To this end, multiple groups have successfully leveraged cancer-specific plectin’s (CSP) abundant and bioavailable expression to guide imaging agents and drug delivery systems [ 13 , 15 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Moreover, recent studies have revealed the anti-cancer effect of direct therapeutic targeting of CSP and plectin, opening new avenues of research into CSP’s and plectin’s role in cancer [ 25 , 26 , 27 ]. Here, we review the current understanding of plectin’s critical role in cancer biology, its diagnostic capabilities, and its therapeutic potential, all of which underscore its far-reaching biologic significance and clinical utility.…”