Proteotoxic stress-induced apoptosis in cancer cells: understanding the susceptibility and enhancing the potency

Abstract

Leiomyosarcoma (LMS) is aggressive cancer with few therapeutic options. LMS cells are more sensitive to proteotoxic stress compared to normal smooth muscle cells. We used small compound 2c to induce proteotoxic stress and compare the transcriptomic adaptations of immortalized human uterine smooth muscle cells (HUtSMC) and LMS cells SK-UT-1. We found that the expression of the heat shock proteins (HSPs) gene family is upregulated with higher efficiency in normal cells. In contrast, the upregulation of BH3-only proteins is higher in LMS cells. HSF1, the master regulator of HSP transcription, is sequestered into transcriptionally incompetent nuclear foci only in LMS cells, which explains the lower HSP upregulation. We also found that several compounds can enhance the cell death response to proteotoxic stress. Specifically, when low doses were used, an inhibitor of salt-inducible kinases (SIKs) and the inhibitor of IRE1α, a key element of the unfolded protein response (UPR), support proteotoxic-induced cell death with strength in LMS cells and without effects on the survival of normal cells. Overall, our data provide an explanation for the higher susceptibility of LMS cells to proteotoxic stress and suggest a potential option for co-treatment strategies.

LSD Modulates Proteins Involved in Cell Proteostasis, Energy Metabolism and Neuroplasticity in Human Cerebral Organoids

“…Furthermore, the enrichment of 'cellular responses to stress' and 'apoptosis' may stem from the abundant number of proteins involved in the proteostasis network, as ribosomal and proteasomal proteins. Various components of this network respond to proteotoxic stress, significantly influencing cellular decisions between apoptosis and survival (36)(37)(38). Thus, fundamentally, the regulation of the proteostasis network profoundly affects both the composition and functionality of the cellular proteome.…”

In Vitro and In Vivo Evaluation of the Effects of Drug 2c and Derivatives on Ovarian Cancer Cells

“…Notably, we observed (data not shown) that the fluorescently labelled 2c used for uptake studies, displayed no activity; we believe this depends on the steric hindrance of the fluorochrome which may impair 2c docking to the catalytic site of the target enzyme. The microscopic examination of the 2c-treated cells showed (Figure S2) a widespread cytoplasmic vacuolization possibly as a consequence of ER-stress [9,23], cell volume alteration and cell membrane deformation; these morphological alterations resemble those of apoptotic cells. Thus, the possible pro-apoptotic effect of 2c was investigated.…”

“…The compounds synthesized in this work (Table 1) can be grouped into two categories. The first set includes the parent compound 2c (1), alkyl and aryl carbamates (2-6) and derivatives (7)(8)(9) that are expected to be ionized at physiological pH. The second set includes compounds in which the parent 2c is linked to an amino acid.…”

“…This process is essential for controlling many vital cellular processes especially in cancer cells, which tend to accumulate altered proteins that must be rapidly degraded. Thus, UPS impairment causes the accumulation of polyubiquitinated proteins leading to proteotoxic stress and cell apoptosis [6,9]. While cysteine-dependent DUBs are not the unique target of 2c, inhibition of the UPS is likely the major component of the observed antitumor activity [10].…”

Selection forces underlying aneuploidy patterns in cancer

“…One approach being explored is targeting the specific vulnerabilities associated with aneuploid chromosomes in general, such as proteotoxic stress, 120 , 121 DNA damage response, 122 or sphingolipid synthesis. 123 In addition, therapies based on specific frequent aneuploidies may hold promise as personalized therapeutic strategies.…”