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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Clofazimine Treatment Modulates Key Non-Coding RNAs Associated with Tumor Progression and Drug Resistance in Lethal
Sarah Batten1, Harish Kumar1,2, Jeremiah Pfitzer1
1Department of Drug Discovery & Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA.
Abstract:
Metastatic castration-resistant prostate cancer/PCa (mCRPC) is a clinically advanced form of PCa that is associated with increased aggressiveness, cancer stemness, morbidity, and the risk of developing resistance to taxanes, currently the first-line chemotherapy for mCRPC. Clofazimine (CLF) is a potential immunomodulator drug that is FDA-approved for the treatment of leprosy. Recently, using in vitro, in vivo, and ex vivo models, we established the efficacy of CLF in chronic myeloid leukemia and multiple myeloma. Here, we demonstrate that CLF is effective as a single agent and in combination with taxanes in a panel of cell lines representing the diversity of CRPC patients. Using a microfluidic assay, we showed the impact of CLF on cancer cell migration and metastatic potential. Further, we also found that CLF reduces ALDH activity-a marker for cancer 'stem-like' cells (CSCs), a subtype of cancer cells with self-renewal and differentiation capacities (epithelial-to-mesenchymal transdifferentiation/EMT). Bulk and single-cell RNAseq followed by functional validation and in silico analysis showed that CLF treatment is associated with apoptosis, ER stress, oxidative phosphorylation, and mitochondrial dysfunction. Most importantly, CLF modulates the expression of several non-coding RNAs, including MALAT1 and NEAT1, that are linked to tumor cell proliferation, cell migration, and drug resistance.
Insights
Clofazimine (CLF) shows promise in treating advanced prostate cancer (PCa) by reducing cancer cell migration and stemness. This FDA-approved drug is effective alone or with taxanes, offering a new therapeutic avenue for metastatic castration-resistant PCa.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) presents significant clinical challenges, including increased aggressiveness and resistance to standard therapies like taxanes.
- Cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) contribute to mCRPC progression and treatment resistance.
- Clofazimine (CLF), an FDA-approved drug for leprosy, has demonstrated efficacy in other hematologic malignancies.
Purpose of the Study:
- To evaluate the efficacy of Clofazimine (CLF) as a single agent and in combination with taxanes for treating diverse mCRPC patient cell lines.
- To investigate the impact of CLF on prostate cancer cell migration, stemness (ALDH activity), and epithelial-to-mesenchymal transition (EMT).
- To elucidate the molecular mechanisms underlying CLF's anti-cancer effects in mCRPC.
Main Methods:
- Utilized a panel of mCRPC cell lines representing patient diversity.
- Employed microfluidic assays to assess cancer cell migration and metastatic potential.
- Measured aldehyde dehydrogenase (ALDH) activity as a marker for cancer stem cells (CSCs).
- Performed bulk and single-cell RNA sequencing (RNAseq), functional validation, and in silico analysis.
Main Results:
- CLF demonstrated efficacy as a single agent and in combination with taxanes against mCRPC cell lines.
- CLF significantly reduced cancer cell migration and metastatic potential.
- CLF decreased ALDH activity, indicating a reduction in cancer stem-like cells (CSCs).
- RNAseq analysis revealed that CLF induces apoptosis, ER stress, and mitochondrial dysfunction, while modulating non-coding RNAs like MALAT1 and NEAT1.
Conclusions:
- Clofazimine (CLF) is a potent therapeutic agent against metastatic castration-resistant prostate cancer (mCRPC), both alone and in combination with taxanes.
- CLF targets key drivers of mCRPC progression, including cancer cell migration, stemness, and EMT.
- The molecular mechanisms involve apoptosis induction, ER stress, mitochondrial dysfunction, and modulation of critical non-coding RNAs, highlighting CLF's potential in overcoming drug resistance.
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