Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

Dirat, Béatrice; Ader, Isabelle; Golzio, Muriel; Massa, Fabienne; Mettouchi, Amel; Laurent, Kathiane; Larbret, Frédéric; Malavaud, Bernard; Cormont, Mireille; Lemichez, Emmanuel; Cuvillier, Olivier; Tanti, Jean‐François; Bost, Fréd́eric

doi:10.1158/1535-7163.mct-14-0102

Cited by 38 publications

(56 citation statements)

References 60 publications

(71 reference statements)

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“…21 Previous studies demonstrated that metformin restrained prostate cancer cell proliferation, migration, and invasion and enhanced apoptosis. 13,22 These findings are consistent with our results. In contrast, Miyoshi et al suggested that metformin inhibited the growth of hepatoma cells by inducing G1 cell cycle arrest.…”

Section: Discussionsupporting

confidence: 93%

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Chen

et al. 2016

Cancer Biology & Therapy

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Metformin has been reported to inhibit the growth of various types of cancers, including prostate cancer. Yet the mode of anti-cancer action of metformin and the underlying mechanisms remain not fully elucidated. We hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of pigment epithelium-derived factor (PEDF) expression in prostate cancer cells. In this report, metformin treatment significantly inhibited the proliferation and colony formation of prostate cancer cells, in a dose-and time-dependent manner. Meanwhile, Metformin markedly suppressed migration and invasion and induced apoptosis of both LNCaP and PC3 cancer cells. Metformin also reduced PC3 tumor growth in BALB/c nude mice in vivo. Furthermore, metformin treatment was associated with higher PEDF expression in both prostate cancer cells and tumor tissue. Taken together, metformin inhibits prostate cancer cell proliferation, migration, invasion and tumor growth, and these activities are mediated by upregulation of PEDF expression. These findings provide a novel insight into the molecular functions of metformin as an anticancer agent.Abbreviations: PEDF, pigment epithelium-derived factor; AMPK, 5 0 -AMP-activated protein kinase; mTOR, mammalian target of rapamycin; IL8, interleukin8; MAPK, mitogen-activated protein kinase; Met, metformin; qPCR, quantitative polymerase chain reaction; PBS, fetal bovine serum; CCK8, Cell Counter Kit-8; PBS, phosphate-buffered saline solution; PtdIns, propidium iodide; SD, standard deviation

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Section: Discussionsupporting

confidence: 93%

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Chen

et al. 2016

Cancer Biology & Therapy

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“…50,51 We showed that cells expressing VAV1-GSS were exquisitely sensitive to azathioprine, which inhibits activation of RAC1 but not of CDC42 or RHOA, 33,34 Other clinically available drugs that inhibit RAC1 and have been proposed to be repurposed as anticancer agents include metformin, statins such as simvastatin, and R-ketorolac. [52][53][54] RAC1 small molecule inhibitors are in ongoing development. 55,56 Taken together, these data suggest RAC1 inhibition is a potential therapeutic strategy for PTCLs with VAV1 fusions, noting, however, that these fusions are present in the minority of PTCLs.…”

Section: Discussionmentioning

confidence: 99%

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Boddicker¹,

Razidlo

Dasari

et al. 2016

Blood

100

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Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of T-cell malignancies that generally demonstrate aggressive clinical behavior, often are refractory to standard therapy, and remain significantly understudied. The most common World Health Organization subtype is PTCL, not otherwise specified (NOS), essentially a “wastebasket” category because of inadequate understanding to assign cases to a more specific diagnostic entity. Identification of novel fusion genes has contributed significantly to improving the classification, biologic understanding, and therapeutic targeting of PTCLs. Here, we integrated mate-pair DNA and RNA next-generation sequencing to identify chromosomal rearrangements encoding expressed fusion transcripts in PTCL, NOS. Two of 11 cases had novel fusions involving VAV1, encoding a truncated form of the VAV1 guanine nucleotide exchange factor important in T-cell receptor signaling. Fluorescence in situ hybridization studies identified VAV1 rearrangements in 10 of 148 PTCLs (7%). These were observed exclusively in PTCL, NOS (11%) and anaplastic large cell lymphoma (11%). In vitro, ectopic expression of a VAV1 fusion promoted cell growth and migration in a RAC1-dependent manner. This growth was inhibited by azathioprine, a clinically available RAC1 inhibitor. We also identified novel kinase gene fusions, ITK-FER and IKZF2-ERBB4, as candidate therapeutic targets that show similarities to known recurrent oncogenic ITK-SYK fusions and ERBB4 transcript variants in PTCLs, respectively. Additional novel and potentially clinically relevant fusions also were discovered. Together, these findings identify VAV1 fusions as recurrent and targetable events in PTCLs and highlight the potential for clinical sequencing to guide individualized therapy approaches for this group of aggressive malignancies.

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“…HMGA2 is a transcription factor that plays major roles in the acquisition of cancer stemness phenotypes and tumorigenicity of malignant neoplasms. Elevated HMGA2 level was significantly associated with poor clinical prognosis for gastric cancer [11]. HMGA2 protein was found to be highly expressed in human OSCC, and its expression was suggested to act as a useful predictive and prognostic tool in clinical management of oral carcinomas [2].…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies found that HMGA2 plays a key role in tumorigenesis. HMGA2, a known oncogene, expression is extremely low in normal adult tissues, while HMGA2 overexpression has been frequently detected in several malignant neoplasms, such as gastric cancer, oral squamous cell carcinoma, colon cancer, pancreatic cancer, and ovarian cancer [2,6,[10][11][12][13][14]. HMGA2 is a transcription factor that plays major roles in the acquisition of cancer stemness phenotypes and tumorigenicity of malignant neoplasms.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of HMGA2 inhibits cellular proliferation and invasion, improves cellular apoptosis in prostate cancer

et al. 2015

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Prostate cancer is the most commonly diagnosed cancer among men and is the second leading cause of cancer-associated deaths among men in the world. Unfortunately, treatment failures are common due to the metastasis and chemoresistance, but the underlying molecular mechanism remains unclear. Accumulating evidence has indicated that the deregulation of DNA-binding protein High Mobility Group A2 (HMGA2) is associated with the development and progression of cancer. This study aimed to explore the expression of HMGA2 in prostate cancer tissues and its correlation to the clinical pathology of prostate cancer, and to discuss the role of HMGA2 in the development of prostate cancer. The results showed that the expression of HMGA2 messenger RNA (mRNA) in the prostate cancer tissues and cells was significantly higher than that in normal prostate tissues and cells (p < 0.05), and the positive expression rate of HMGA2 mRNA in the prostate cancer tissues from patients with positive lymph node metastasis or with high Gleason grade was significantly higher than that from patients with negative lymph node metastasis or with low Gleason grade (p < 0.05). In order to explore the role of HMGA2 in prostate cancer, the expression of HMGA2 in the human prostate cancer PC3 cell line was downregulated by RNA interference. Then, the changes in proliferation, apoptosis, invasion, and migration of PC3 cells were examined by MTT test, PI staining, Annexin V-FITC staining, and Transwell chamber assay. Results showed that the abilities of proliferation, invasion, and migration were suppressed in HMGA2 knockdown PC3 cells, and the abilities of apoptosis were enhanced in HMGA2 knockdown PC3 cells. The expression of cyclin A and vimentin was downregulated in HMGA2 knockdown PC3 cells, and the expression of caspase 3 and E-cadherin was upregulated in HMGA2 knockdown PC3 cells. Taken together, the overexpression of HMGA2 in prostate cancer might be related to the tumorigenesis, invasion, and metastasis of prostate cancer, the downregulation of HMGA2 could inhibit cellular proliferation, invasion, and metastasis, and improve cellular apoptosis in prostate cancer, which might be a potential target for the treatment of prostate cancer.

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Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

Cited by 38 publications

References 60 publications

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

Downregulation of HMGA2 inhibits cellular proliferation and invasion, improves cellular apoptosis in prostate cancer

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