Cyclopamine tartrate, a modulator of hedgehog signaling and mitochondrial respiration, effectively arrests lung tumor growth and progression

Sarada Preeta Kalainayakan, Poorva Ghosh, Sanchareeka Dey, Keely E. Fitzgerald, Sagar Sohoni, Purna Chaitanya Konduri, Massoud Garrossian, Li Liu, Li Zhang

Research output: Contribution to journalArticle

Abstract

Lung cancer remains the leading cause of cancer-related death, despite the advent of targeted therapies and immunotherapies. Therefore, it is crucial to identify novel molecular features unique to lung tumors. Here, we show that cyclopamine tartrate (CycT) strongly suppresses the growth of subcutaneously implanted non-small cell lung cancer (NSCLC) xenografts and nearly eradicated orthotopically implanted NSCLC xenografts. CycT reduces heme synthesis and degradation in NSCLC cells and suppresses oxygen consumption in purified mitochondria. In orthotopic tumors, CycT decreases the levels of proteins and enzymes crucial for heme synthesis, uptake, and oxidative phosphorylation (OXPHOS). CycT also decreases the levels of two regulators promoting OXPHOS, MYC and MCL1, and effectively alleviates tumor hypoxia. Evidently, CycT acts via multiple modes to suppress OXPHOS. One mode is to directly inhibit mitochondrial respiration/OXPHOS. Another mode is to inhibit heme synthesis and degradation. Both modes appear to be independent of hedgehog signaling. Addition of heme to NSCLC cells partially reverses the effect of CycT on oxygen consumption, proliferation, and tumorigenic functions. Together, our results strongly suggest that CycT suppress tumor growth in the lung by inhibiting heme metabolism and OXPHOS. Targeting heme metabolism and OXPHOS may be an effective strategy to combat lung cancer.

Original languageEnglish (US)
Article number1405
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Oxidative Phosphorylation
Heme
Respiration
Lung
Non-Small Cell Lung Carcinoma
Growth
Neoplasms
Heterografts
Oxygen Consumption
Lung Neoplasms
tartaric acid
cyclopamine
Immunotherapy
Mitochondria
Enzymes
Proteins

ASJC Scopus subject areas

  • General

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Cyclopamine tartrate, a modulator of hedgehog signaling and mitochondrial respiration, effectively arrests lung tumor growth and progression. / Kalainayakan, Sarada Preeta; Ghosh, Poorva; Dey, Sanchareeka; Fitzgerald, Keely E.; Sohoni, Sagar; Konduri, Purna Chaitanya; Garrossian, Massoud; Liu, Li; Zhang, Li.

In: Scientific Reports, Vol. 9, No. 1, 1405, 01.12.2019.

Research output: Contribution to journalArticle

Kalainayakan, Sarada Preeta ; Ghosh, Poorva ; Dey, Sanchareeka ; Fitzgerald, Keely E. ; Sohoni, Sagar ; Konduri, Purna Chaitanya ; Garrossian, Massoud ; Liu, Li ; Zhang, Li. / Cyclopamine tartrate, a modulator of hedgehog signaling and mitochondrial respiration, effectively arrests lung tumor growth and progression. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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