Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer.

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.

EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.

Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor SP1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.

Demystifying the CXCR4 conundrum in cancer biology: Beyond the surface signaling paradigm.

The oncogenic chemokine duo CXCR4-CXCL12/SDF-1 (C-X-C Receptor 4-C-X-C Ligand 12/ Stromal-derived factor 1) has been the topic of intense scientific disquisitions since Muller et al., in her ground-breaking research, described this axis as a critical determinant of organ-specific metastasis in breast cancer. Elevated CXCR4 levels correlate with distant metastases, poor prognosis, and unfavourable outcomes in most solid tumors. Therapeutic impediment of the axis in clinics with Food and Drug Administration (FDA) approved inhibitors like AMD3100 or Plerixafor yield dubious results, contrary to pre-clinical developments. Clinical trials entailing inhibition of CXCR7 (C-X-C Receptor 7), another convicted chemokine receptor that exhibits affinity for CXCL12, reveal outcomes analogous to that of CXCR4-CXCL12 axis blockade. Of note, the cellular CXCR4 knockout phenotype varies largely from that of inhibitor treatments. These shaky findings pique great curiosity to delve further into the realm of this infamous chemokine receptor to provide a probable explanation. A multitude of recent reports suggests the presence of an increased intracellular CXCR4 pool in various cancers, both cytoplasmic and nuclear. This intracellular CXCR4 protein reserve seems active as it correlates with vital tumor attributes, viz. prognosis, aggressiveness, metastasis, and disease-free survival. Diminishing this entire intracellular CXCR4 load apart from the surface signals looks encouraging from a therapeutic point of view. Transcending beyond the classically accepted concept of ligand-mediated surface signaling, this review sheds new light on plausible associations of intracellularly compartmentalised CXCR4 with various aspects of tumorigenesis. Besides, this review also puts forward a comprehensive account of CXCR4 regulation in different cancers.

Cytokine chemokine network in tumor microenvironment: Impact on CSC properties and therapeutic applications.

A subpopulation of cells in many cancers has stem cell traits, mediates metastasis, and contributes to treatment resistance. These cells are considered as cancer stem cells (CSCs). CSC properties of tumor cells are immensely regulated by close interactions with tumor microenvironment components such as mesenchymal stem cells, tumor related fibroblasts, adipocytes, endothelial cells, and immune cells via the intricate network of cytokines, chemokines, and growth factors. Inflammatory cytokines including interleukin (IL)-1, IL-6, and IL-8 play a major role in these interactions via the activation of signal transduction pathways like Stat3/NF-κB etc. in stromal and tumor cells. The activation of these pathways increases the release of more cytokines, resulting in positive feedback loops which help in CSC self-renewal. The pathways controlled by these cytokine loops are similar to those that are active during chronic inflammation and wound healing, suggesting that they might have critical role in establishing relationship between inflammation and cancer. Anti-inflammatory drugs have been identified to inhibit these cytokines and their receptor mediated pathways. These agents have the potential to target CSCs by inhibiting signals from the tumor microenvironment and considered to be a potential candidate for future therapeutics. The significance of cytokines released from the tumor microenvironment in different phases of cancer, as well as their potential application in cancer therapeutics is discussed in this article.

Salinomycin inhibits epigenetic modulator EZH2 to enhance death receptors in colon cancer stem cells.

Drug resistance is one of the trademark features of Cancer Stem Cells (CSCs). We and others have recently shown that paucity of functional death receptors (DR4/5) on the cell surface of tumour cells is one of the major reasons for drug resistance, but their involvement in the context of in CSCs is poorly understood. By harnessing CSC specific cytotoxic function of salinomycin, we discovered a critical role of epigenetic modulator EZH2 in regulating the expression of DRs in colon CSCs. Our unbiased proteome profiler array approach followed by ChIP analysis of salinomycin treated cells indicated that the expression of DRs, especially DR4 is epigenetically repressed in colon CSCs. Concurrently, EZH2 knockdown demonstrated increased expression of DR4/DR5, significant reduction of CSC phenotypes such as spheroid formation in-vitro and tumorigenic potential in-vivo in colon cancer. TCGA data analysis of human colon cancer clinical samples shows strong inverse correlation between EZH2 and DR4. Taken together, this study provides an insight about epigenetic regulation of DR4 in colon CSCs and advocates that drug-resistant colon cancer can be therapeutically targeted by combining TRAIL and small molecule EZH2 inhibitors.

Catalyst-free facile synthesis of polycyclic indole/pyrrole substituted-1,2,3-triazoles.

A general and catalyst-free access to the fused polycyclic N-heterocycles via an intramolecular azide-alkene cascade reaction under mild reaction conditions has been developed. The reaction is applicable to both indole and pyrrole substrates, and a variety of substituents are tolerated. The entire sequence can be carried out in a one-pot operation. This methodology provides a sustainable and efficient access to a variety of novel polycyclic indole/pyrrole substituted-1,2,3-triazoles.