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Intrinsic adaptations in OXPHOS power output and reduced tumorigenicity characterize doxorubicin resistant ovarian cancer cells.

ABSTRACT: Although the development of chemoresistance is multifactorial, active chemotherapeutic efflux driven by upregulations in ATP binding cassette (ABC) transporters are commonplace. Chemotherapeutic efflux pumps, like ABCB1, couple drug efflux to ATP hydrolysis and thus potentially elevate cellular demand for ATP resynthesis. Elevations in both mitochondrial content and cellular respiration are common phenotypes accompanying many models of cancer cell chemoresistance, including those dependent on ABCB1. The present study set out to characterize potential mitochondrial remodeling commensurate with ABCB1-dependent chemoresistance, as well as investigate the impact of ABCB1 activity on mitochondrial respiratory kinetics. To do this, comprehensive bioenergetic phenotyping was performed across ABCB1-dependent chemoresistant cell models and compared to chemosensitive controls. In doxorubicin (DOX) resistant ovarian cancer cells, the combination of both increased mitochondrial content and enhanced respiratory complex I (CI) boosted intrinsic oxidative phosphorylation (OXPHOS) power output. With respect to ABCB1, acute ABCB1 inhibition partially normalized intact basal mitochondrial respiration between chemosensitive and chemoresistant cells, suggesting that active ABCB1 contributes to mitochondrial remodeling in favor of enhanced OXPHOS. Interestingly, while enhanced OXPHOS power output supported ABCB1 drug efflux when DOX was present, in the absence of chemotherapeutic stress, enhanced OXPHOS power output was associated with reduced tumorigenicity.

SUBMITTER: Hagen JT

PROVIDER: S-EPMC9661894 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Intrinsic adaptations in OXPHOS power output and reduced tumorigenicity characterize doxorubicin resistant ovarian cancer cells.

Hagen James T JT Montgomery McLane M MM Biagioni Ericka M EM Krassovskaia Polina P Jevtovic Filip F Shookster Daniel D Sharma Uma U Tung Kang K Broskey Nickolas T NT May Linda L Huang Hu H Brault Jeffrey J JJ Neufer P Darrell PD Cabot Myles C MC Fisher-Wellman Kelsey H KH

Biochimica et biophysica acta. Bioenergetics 20220902 8

Although the development of chemoresistance is multifactorial, active chemotherapeutic efflux driven by upregulations in ATP binding cassette (ABC) transporters are commonplace. Chemotherapeutic efflux pumps, like ABCB1, couple drug efflux to ATP hydrolysis and thus potentially elevate cellular demand for ATP resynthesis. Elevations in both mitochondrial content and cellular respiration are common phenotypes accompanying many models of cancer cell chemoresistance, including those dependent on AB ...[more]

PMID: 36058252

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Project description:The pectoralis muscles of the blue-breasted quail Coturnix chinensis generate the highest power output over a contraction cycle measured to date, approximately 400 W kg- 1. The power generated during a cyclical contraction is the product of work and cycle frequency (or standard operating frequency), suggesting that high powers should be favoured by operating at high cycle frequencies. Yet the quail muscles operate at an intermediate cycle frequency (23 Hz), which is much lower than the highest frequency skeletal muscles are capable of operating (~ 200 Hz in vertebrates). To understand this apparent anomaly, in this paper I consider the adaptations that favour high mechanical power as well as the trade-offs that occur between force and muscle operating frequency that limit power. It will be shown that adaptations that favour rapid cyclical contractions compromise force generation; consequently, maximum power increases with cycle frequency to approximately 15-25 Hz, but decreases at higher cycle frequencies. At high cycle frequencies, muscle stress is reduced by a decrease in the crossbridge duty cycle and an increase in the proportion of the muscle occupied by non-contractile elements such as sarcoplasmic reticulum and mitochondria. Muscles adapted to generate high powers, such as the pectoralis muscle of blue-breasted quail, exhibit: (i) intermediate contraction kinetics; (ii) a high relative myofibrillar volume; and (iii) a high maximum shortening velocity and a relatively flat force-velocity relationship. They are also characterised by (iv) operating at an intermediate cycle frequency; (v) utilisation of asymmetrical length trajectories, with a high proportion of the cycle spent shortening; and, finally, (vi) relatively large muscles. In part, the high power output of the blue-breasted quail pectoralis muscle can be attributed to its body size and the intermediate wing beat frequency required to generate aerodynamic force to support body mass, but in addition specialisations in the contractile and morphological properties of the muscle favour the generation of high stress at high strain rates.

Dataset Information

Intrinsic adaptations in OXPHOS power output and reduced tumorigenicity characterize doxorubicin resistant ovarian cancer cells.

Publications

Intrinsic adaptations in OXPHOS power output and reduced tumorigenicity characterize doxorubicin resistant ovarian cancer cells.

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