Summary:
Recent reports ind icate hypoxia influences the circadian clock through
the transcriptional activities of hypoxia inducible factors (HIFs) at clock
genes. Unexpectedly, we uncover a profound disruption of the circadian clock and
diurnal transcriptome when hypoxic cells are permitted to acidify,
recapitulating the tumor microenvironment. Buffering against acidification or
inhibiting lactic acid production fully rescues circadian oscillation.
Acidification of several human and murine cell lines, as well as primary murine
T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1)
signaling, a key regulator of translation in response to metabolic status. We
find acid drives peripheral redistribution of normally perinuclear lysosomes
away from perinuclear RHEB, inhibiting lysosome-bound mTOR activity. Restoring
mTORC1 signaling and the translation it governs rescues clock oscillation,
revealing a model in which acid produced during the cellular metabolic response
to hypoxia suppresses the circadian clock through diminished translation of
clock constituents.
These data provide low incidences for adverse events in a large series of DBS surgeries for movement disorders at up to 10 years follow-up. Accurate estimates of adverse events will better inform patients and caregivers about the potential risks and benefits of surgery and provide normative data for process improvement.
Circadian rhythms are an integral part of physiology, underscoring their relevance for the treatment of disease. We conducted cell-based high-throughput screening to investigate time-of-day influences on the activity of known antitumor agents and found that many compounds exhibit daily rhythms of cytotoxicity concomitant with previously reported oscillations of target genes. Rhythmic action of HSP90 inhibitors was mediated by specific isoforms of HSP90, genetic perturbation of which affected the cell cycle. Furthermore, clock mutants affected the cell cycle in parallel with abrogating rhythms of cytotoxicity, and pharmacological inhibition of the cell cycle also eliminated rhythmic drug effects. An HSP90 inhibitor reduced growth rate of a mouse melanoma in a time-of-day–specific manner, but efficacy was impaired in clock-deficient tumors. These results provide a powerful rationale for appropriate daily timing of anticancer drugs and suggest circadian regulation of the cell cycle within the tumor as an underlying mechanism.
The circadian molecular clock regulates and coordinates cellular metabolism with the organism's daily feeding and fasting cycle. Disruption of circadian rhythm, such as through jet lag or shift work, appears to heighten cancer risk in humans and accelerates tumorigenesis in animal models. The mammalian clock is a circuitry of transcription factors anchored by BMAL1-CLOCK, which drives diurnal oscillation of metabolic gene expression. The clock is independent of the cell cycle, but they can couple to coordinate normal cell proliferation. Expression of components of the clock, BMAL1 and PER2, appears decreased in human cancers. PER2 promotes p53 function, while BMAL1 expression is suppressed by MYC, linking key oncogenic drivers to the circadian clock. This review provides an overview of the clock, its regulation of metabolism, the connection to cancer shown in studies spanning from human epidemiology to cell biology, and the therapeutic implications of the circadian rhythm.
Acidity, generated in hypoxia or hypermetabolic states, perturbs homeostasis and is a feature of solid tumors. That acid peripherally disperses lysosomes is a three-decade-old observation, yet one little understood or appreciated. However, recent work has recognized the inhibitory impact this spatial redistribution has on mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of metabolism. This finding argues for a paradigm shift in localization of mTORC1 activator Ras homolog enriched in brain (RHEB), a conclusion several others have now independently reached. Thus, mTORC1, known to sense amino acids, mitogens, and energy to restrict biosynthesis to times of adequate resources, also senses pH and, via dampened mTORgoverned synthesis of clock proteins, regulates the circadian clock to achieve concerted responses to metabolic stress. While this may allow cancer to endure metabolic deprivation, immune cell mTOR signaling likewise exhibits pH sensitivity, suggesting that suppression of antitumor immune function by solid tumor acidity may additionally fuel cancers, an obstacle potentially reversible through therapeutic pH manipulation.
A baiting system suitable for the delivery of oral rabies vaccine to dog populations in developing countries was studied in Zimbabwe. In a field trial, 369 sponge baits containing a placebo liquid, rhodamine B as a biomarker and a pungent attractant were distributed over an area of 60 sq km in a communal land in Manicaland with a dog population of over 500. Twenty-four hours later 21 per cent of the baits were recovered and 79 per cent of these had been significantly bitten or chewed. Twenty-five per cent of the dogs examined showed evidence of superficial staining by rhodamine B indicating that they had chewed baits or ingested their contents. It was concluded that the system would deliver an oral vaccine to dog populations more efficiently than had been the case in comparable studies in wildlife populations, but that the number of baits per unit area should in future studies be increased.
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