Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance

Shi, Lei; Wang, Siqing; Zangari, Maurizio; Xu, Hui; Cao, Thai M.; Xu, Chunjiao; Wu, Yi; Xiao, Fang; Liu, Yanping; Yang, Ye; Salama, Mohamed E.; Li, Guiyuan; Tricot, Guido; Zhan, Fenghuang

doi:10.18632/oncotarget.105

Cited by 100 publications

(104 citation statements)

References 44 publications

(54 reference statements)

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“…CDC28 kinase subunit 1 (CKS1B) is a necessary cofactor of the CRL complex, SCF Skp2 , which regulates cellular entry into S phase and possesses anti-apoptotic activity through p27-dependent and -independent pathways, and is a critical factor in MM drug resistance (5). CKS1B is an essential protein for normal cell division and growth (6), and is expressed at a high level in various cancer tissues including hepatocellular carcinoma (7), colon (8), lung (9), oral squamous cell carcinoma (10), breast cancer (11), and others.…”

Section: Introductionmentioning

confidence: 99%

NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma

Huang

Zhou

Thomas

et al. 2015

Clinical Cancer Research

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Purpose CKS1B is significantly upregulated in multiple myeloma (MM) and associated with poor prognosis. The identification of novel therapies is essential for effective treatment of patients resistant to chemotherapy. The NEDD8 inhibitor MLN4924 selectively targets SCFSkp2 activation and offers a more specific approach to protein degradation inhibition than total proteasomal inhibition. The goal of this study was to evaluate whether MLN4924 is effective in high CKS1B conditions and identify mechanisms regulating drug potency. Experimental Design Bortezomib and MLN4924 sensitivity was assessed through proliferation, viability, clonogenic potential, and senescence induction in cells overexpressing CKS1B. The mechanism for MLN4924 sensitivity was elucidated by immunoblot analysis of SCFskp substrates and confirmed by shRNA knockdown. The clinical relevance of the NEDD8 pathway was examined in GEPs derived from healthy people, patients with MGUS, and MM. Results Cells overexpressing CKS1B were resistant to bortezomib but sensitive to MLN4924. Treatment of CKS1B-overexpressing cells with MLN4924 decreased proliferation, clonogenicity, and induced senescence. MLN4924, but not bortezomib, induced stabilization of p21 and knockdown of p21 resulted in loss of MLN4924 sensitivity. Patients with MGUS and MM exhibited increased expression of NEDD8-pathway genes relative to normal plasma cells. MM patients with high NEDD8 expression were linked to bortezomib resistance in clinical trials, and had inferior outcomes. Conclusions Our data demonstrate cells with elevated CKS1B expression are resistant to bortezomib but sensitive to MLN4924 and offer a mechanism through the stabilization of p21. These findings provide rationale for targeting the NEDD8 pathway in MM patients exhibiting elevated expression of CKS1B.

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Section: Introductionmentioning

confidence: 99%

NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma

Huang

Zhou

Thomas

et al. 2015

Clinical Cancer Research

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“…In these cells, activation of the STAT3 protein is a reversible, tightly controlled process that typically lasts for a limited duration [16]. Conversely, the persistent activation of the STAT3 protein is detected at high frequency in a large number of human malignancies [17, 18, 19, 20]. Aberrantly active STAT3 contributes to oncogenesis by preventing apoptosis, inducing cell proliferation and suppressing anti-tumor immune responses [16].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of STAT3 signaling targets both tumor-initiating and differentiated cell populations in prostate cancer

Han

Wang

et al. 2014

Oncotarget

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Despite of tremendous research efforts to profile prostate cancer, the genetic alterations and biological processes that correlate with disease progression remain partially elusive. In this study we show that the STAT3 small molecule inhibitor Stattic caused S-phase accumulation at low-dose levels and led to massive apoptosis at a relatively high-dose level in prostate cancer cells. STAT3 knockdown led to the disruption of the microvascular niche which tumor-initiating cells (TICs) and non-tumor initiating cells (non-TICs)depend on. Primary human prostate cancer cells and prostate cancer cell line contained high aldehyde dehydrogenase activity (ALDHhigh) subpopulations with stem cell-like characteristics, which expressed higher levels of the active phosphorylated form of STAT3 (pSTAT3) than that of non-ALDHhigh subpopulations. Stattic could singnificantly decreas the population of ALDHhigh prostate cancer cells even at low-dose levels. IL-6 can convert non-ALDHhigh cells to ALDHhigh cells in prostate cancer cell line as well as from cells derived from human prostate tumors, the conversion mediated by IL-6 was abrogated in the presence of STAT3 inhibitor or upon STAT3 knockdown. STAT3 knockdown significantly impaired the ability of prostate cancer cells to initiate development of prostate adenocarcinoma. Moreover, blockade of STAT3 signaling was significantly effective in eradicating the tumor-initiating and bulk tumor cancer cell populations in both prostate cancer cell-line xenograft model and patient-derived tumor xenograft (PDTX) models. This data suggests that targeting both tumor initiating and differentiated cell populations by STAT3 inhibition is predicted to have greater efficacy for prostate cancer treatment.

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“…ERK activity has also been associated with endocrine therapy resistance and decreased survival of breast cancer patients [4]. Pharmacological inhibition of ERK activity in vitro has been shown to reverse the tamoxifen resistant phenotype in breast [10] and several other cancer types [11, 12]. …”

Section: Introductionmentioning

confidence: 99%

Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity

Haagenson

Zhang

et al. 2014

Oncotarget

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Increased activation of ERK signaling has been reported in breast cancer models of acquired tamoxifen resistance. Here, we examined the expression of Mitogen-Activated Protein Kinase Phosphatases (MKPs) 1 and 2 following tamoxifen treatment and the effects of MKP-1/MKP-2 overexpression on tamoxifen sensitivity. Treatment of MCF7 breast cancer cells with tamoxifen increased MKP-2, but not MKP-1, protein levels. Overexpression of MKP-1 or MKP-2 inhibited estrogen-induced MCF7 cell proliferation compared to vector controls. MCF7-MKP-2 cells displayed significantly increased sensitivity to tamoxifen as compared to vector control or MCF7-MKP-1 cells. MKP-1 or MKP-2 overexpression eliminated ERK1/2 phosphorylation, suggesting that decreases in estrogen-induced proliferation of MKP-1 and MKP-2 overexpressing cells are due to ERK1/2 dephosphorylation. JNK1/2 activation was not detectable in any of these cells. These data suggest that tamoxifen-induced death of these cells is not dependent upon JNK signaling, but rather that ERK is the major MAPK driving their proliferation. MCF7-TAMR cells express higher levels of MKP-2 mRNA and protein than MCF7 cells. MKP-2 and phospho-ERK1/2 proteins are constitutively expressed in MCF7-TAMR cells, and activated JNK1/2 is not detectable. These data suggest that MKP-2 rather than MKP-1 is tamoxifen-regulated and that the elevated expression of MKP-2 in MCF7-TAMR cells potentially functions to restore tamoxifen sensitivity.

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Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance

Cited by 100 publications

References 44 publications

NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma

NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma

Inhibition of STAT3 signaling targets both tumor-initiating and differentiated cell populations in prostate cancer

Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity

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