Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells

Rohira, Aarti D.; Yan, Fei; Wang, Lei; Wang, Jin; Zhou, Suoling; Lu, Andrew; Yu, Yang; Xu, Jianming; Lonard, David M.; O’Malley, Bert W.

doi:10.1158/0008-5472.can-16-2982

Cited by 39 publications

(54 citation statements)

References 48 publications

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“…Consequently, SRC-3 regulates multiple physiological and pathophysiologic actions. 40,41 Our study demonstrated that SRC-3 deficiency impaired IGF-1 signaling from several aspects, thereby affecting platelet production induced by IGF-1. Moreover, the expression of IGF-binding protein 3 is also downregulated when SRC-3 is abolished, resulting in decreased serum IGF-1.…”

Section: Discussionmentioning

confidence: 74%

IGF-1 facilitates thrombopoiesis primarily through Akt activation

Chen

Shen

et al. 2018

Blood

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It is known that insulin-like growth factor-1 (IGF-1) also functions as a hematopoietic factor, although its direct effect on thrombopoiesis remains unclear. In this study, we show that IGF-1 is able to promote CD34 cell differentiation toward megakaryocytes (MKs), as well as the facilitation of proplatelet formation (PPF) and platelet production from cultured MKs. The in vivo study demonstrates that IGF-1 administration accelerates platelet recovery in mice after 6.0 Gy of irradiation and in mice that received bone marrow transplantation following 10.0 Gy of lethal irradiation. Subsequent investigations reveal that extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt activation mediate the effect of IGF-1 on thrombopoiesis. Notably, Akt activation induced by IGF-1 is more apparent than that of ERK1/2, compared with that of thrombopoietin (TPO) treatment. Moreover, the effect of IGF-1 on thrombopoiesis is independent of TPO signaling because IGF-1 treatment can also lead to a significant increase of platelet counts in homozygous TPO receptor mutant mice. Further analysis indicates that the activation of Akt triggered by IGF-1 requires the assistance of steroid receptor coactivator-3 (SRC-3). Therefore, our data reveal a distinct role of IGF-1 in regulating thrombopoiesis, providing new insights into TPO-independent regulation of platelet generation.

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Section: Discussionmentioning

confidence: 74%

IGF-1 facilitates thrombopoiesis primarily through Akt activation

Chen

Shen

et al. 2018

Blood

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“…21,22 More recently, SRC-3 was reported to be critical for the maintenance of cancer stemlike cells by promoting the expressions of epithelial-to-mesenchymal transition regulators and stem cell markers. 23 However, the distinct role of SRC-3 in the regulation of HSC maintenance and function remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

SRC-3 is involved in maintaining hematopoietic stem cell quiescence by regulation of mitochondrial metabolism in mice

Zeng

Chen

et al. 2018

Blood

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Quiescence maintenance is an important property of hematopoietic stem cells (HSCs), whereas the regulatory factors and underlying mechanisms involved in HSC quiescence maintenance are not fully uncovered. Here, we show that steroid receptor coactivator 3 (SRC-3) is highly expressed in HSCs, and SRC-3-deficient HSCs are less quiescent and more proliferative, resulting in increased sensitivity to chemotherapy and irradiation. Moreover, the long-term reconstituting ability of HSCs is markedly impaired in the absence of SRC-3, and SRC-3 knockout (SRC-3) mice exhibit a significant disruption of hematopoietic stem and progenitor cell homeostasis. Further investigations show that SRC-3 deficiency leads to enhanced mitochondrial metabolism, accompanied by overproduction of reactive oxygen species (ROS) in HSCs. Notably, the downstream target genes of peroxisome proliferator-activated receptor-coactivators 1α (PGC-1α) involved in the regulation of mitochondrial metabolism are significantly upregulated in SRC-3-deficient HSCs. Meanwhile, a significant decrease in the expression of histone acetyltransferase GCN5 accompanied by downregulation of PGC-1α acetylation is observed in SRC-3-null HSCs. Conversely, overexpression of GCN5 can inhibit SRC-3 deficiency-induced mitochondrial metabolism enhancement and ROS overproduction, thereby evidently rescuing the impairment of HSCs in SRC-3 mice. Collectively, our findings demonstrate that SRC-3 plays an important role in HSC quiescence maintenance by regulating mitochondrial metabolism.

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“…Phosphorylation of SRC-3 Ser857 promotes SRC-3 association with transcription factor ATF4 to mediate non-oxidative pentose phosphate pathway and purine synthesis. This study (35) did not evaluate SRC-3 in the context of CSCs, although SRC-3 has been linked to CSC activity (10,11). ATF4 pathway activation was identified by IPA in our studies (Figure 1) and could explain the correlation between PFKFB4 and PELP1/SRC-3driven CSCs.…”

Section: Discussionmentioning

confidence: 73%

“…xenograft models (10). Our laboratory reported that cytoplasmic complexes composed of PELP1 and SRC-3 mediate breast CSC expansion (11).…”

Section: Introductionmentioning

confidence: 99%

PELP1/SRC-3-dependent regulation of metabolic kinases drives therapy resistant ER+ breast cancer

Truong

Benner

Hagen

et al. 2020

Preprint

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Recurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs frequently exist as a minority population in therapy resistant tumors. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genes PFKFB3 and PFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein-protein interactions with SRC-3. PFKFB inhibitors exhibited combinatorial effects in conjunction with ER targeted therapies in breast cancer cells, including tamoxifen resistant (TamR) and paclitaxel resistant (TaxR) models and ER+ patient-derived organoids (PDxO). Finally, PFKFB4 knockdown resulted in decreased circulating tumor cell (CTC) populations in mammary intraductal (MIND) models. Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cell populations that include CSCs and CTCs. Identifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance.

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Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells

Cited by 39 publications

References 48 publications

IGF-1 facilitates thrombopoiesis primarily through Akt activation

IGF-1 facilitates thrombopoiesis primarily through Akt activation

SRC-3 is involved in maintaining hematopoietic stem cell quiescence by regulation of mitochondrial metabolism in mice

PELP1/SRC-3-dependent regulation of metabolic kinases drives therapy resistant ER+ breast cancer

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