Uncontrollable metastatic outgrowth process is the leading cause of mortality worldwide, even in the case of colorectal cancer. Colorectal cancer (CRC) accounts for approximately 10% of all annually diagnosed cancers and 50% of CRC patients will develop metastases in the course of disease. Most patients with metastatic CRC have incurable disease. Even if patients undergo resection of liver metastases, the 5-year survival rate ranges from 25 to 58%. Next-generation sequencing of tumour specimens from large colorectal cancer patient cohorts has led to major advances in elucidating the genomic landscape of these tumours and paired metastases. The expression profiles of primary CRC and their metastatic lesions at both the gene and pathway levels were compared and led to the selection of early driver genes responsible for carcinogenesis and metastasis-specific genes that increased the metastatic process. The genetic, transcriptional and epigenetic alteration encoded by these genes and their combination influence many pivotal signalling pathways, enabling the dissemination and outgrowth in distant organs. Therapeutic regimens affecting several different active pathways may have important implications for therapeutic efficacy.

Mitochondrial Complex II (CII) activity supports multiple types of respiration and connects metabolic state with succinate signaling. It is therefore unsurprising that CII activity has been linked to biological phenomena that require crosstalk between metabolism and signaling, including neurodegeneration, metabolic shifts in cancer, immune activation, and ischemia reperfusion injury. In each of these processes, CII activity may be regulated at the level of assembly, with the disassembled SDHA subunit stored as metastable species with one or more assembly factors. However, both the exact molecular nature of these species and the mechanism of release of SDHA from these metastable species is unclear. In this work, we identified that transfer of SDHA into CII proceeds through at least three metastable intermediates, we assigned the sequence of appearance of these intermediates, and we determined structures for two of these. A complex between SDHA and one of its assembly factors, succinate dehydrogenase assembly factor 2 (SDHAF2), is likely the main alternative species that accumulates in cells. A second assembly factor, succinate dehydrogenase assembly factor 4 (SDHAF4), must displace SDHAF2 for assembly to proceed. Changes in intrinsic disorder in both SDHAF2 and SDHAF4 are required to release SDHA from the metastable complexes. Evaluation of unrelated biological complexes suggests that changes in disorder may guide post-folding biogenesis during both self-assembly and assisted assembly.

Signal transducer and activator of transcription 3 (STaT3) signalling serves an important role in carcinogenesis and cellular senescence, and its inhibition in tumour cells represents an attractive therapeutic target. Premature cellular senescence, a process of permanent proliferative arrest of cells in response to various inducers, such as cytostatic drugs or ionizing radiation, is accompanied by morphological and secretory changes, and by altered susceptibility to chemotherapeutic agents, which can thereby complicate their eradication by cancer therapies. in the present study, the responsiveness of proliferating and docetaxel (dTX)-induced senescent cancer cells to small molecule STaT3 inhibitor Stattic and its analogues was evaluated using tumour cell lines. These agents displayed cytotoxic effects in cell viability assays on both proliferating and senescent murine TraMP-c2 and Tc-1 cells; however, senescent cells were markedly more resistant. Western blot analysis revealed that Stattic and its analogues effectively inhibited constitutive STaT3 phosphorylation in both proliferating and senescent cells. Furthermore, whether the Stattic-derived inhibitor K1836 could affect senescence induction or modulate the phenotype of senescent cells was evaluated. K1836 treatment demonstrated no effect on senescence induction by dTX. However, the K1836 compound significantly modulated secretion of certain cytokines (interleukin-6, growth-regulated oncogene α and monocyte chemoattractant protein-1). in summary, the present study demonstrated differences between proliferating and senescent tumour cells in terms of their susceptibility to STaT3 inhibitors and demonstrated the ability of the new STaT3 inhibitor K1836 to affect the secretion of essential components of the senescence-associated secretory phenotype. The present study may be useful for further development of STaT3 inhibitor-based therapy of cancer or age-related diseases.

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