Intracellular organelles in cancer

Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

DEAD-box helicase 6 (DDX6), the regulator of P-body assembly, is essential for the survival of acute myeloid leukemia (AML) cells. Here the authors report that DDX6 undergoes phase separation to preserve mRNA subsets in P-bodies, promoting branched-chain amino acid metabolism and chemoresistance in AML.

The early events in ferroptosis are not clear. Here, the authors report that intra-lysosomal lipid peroxidation (LPO) induces lysosomal membrane permeabilization (LMP) and consequent iron leakage, fostering cell-wide LPO and eventually ferroptotic cell death in tumor cells.

Cancer cells rely on mitochondria for energy and macromolecule synthesis. Here, the authors show that RNA G-quadruplex dynamics, driven by oncogenic signals, regulate the translation of nuclear-encoded mitochondrial mRNAs, affecting mitochondrial function and promoting cancer cell growth.

Glioblastoma (GBM) treatment faces challenges due to drug resistance. Here, the authors show that lysine-arginine balance supports lysosomes mediated tolerance to temozolomide and lysine restriction mimetic increases anticancer therapies in GBM preclinical models.

Mutations in the TP53 gene are linked to cancer progression and drug resistance. Here, the authors show that mutant p53 inhibits stress granule formation, leading to increased apoptosis and enhanced sensitivity to the ER stress-inducing chemotherapy drug sorafenib in preclinical models of hepatocellular carcinoma.

Prostate cancer growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). Here the authors find that a histone methyltransferase KMT9 is localized in the mitochondria of prostate cancer cells to regulate PDC activity by methylating its subunit DLAT.

CDK4/6 inhibitors (CDK4/6i) have improved cancer patient outcomes but shown limited benefits for those with triple-negative breast cancer (TNBC). Here, the authors report that CDK4/6 inhibition prevents CDK4 enhanced mitochondria-endoplasmic reticulum interactions, inhibiting mitochondrial apoptosis and driving resistance to CDK4/6i in TNBC models.