p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents.

The Mitogen Activated Protein Kinase (MAPK) signaling plays a critical role in the outcome and the sensitivity to anticancer therapies. Activated MAPK can transmit extracellular signals to regulate cell growth, proliferation, differentiation, migration, apoptosis and so on. Apoptosis as well as macroautophagy (hereafter referred to as autophagy) can be induced by extracellular stimuli such the treatment of chemotherapeutic agents, resulting in different cell response to these drugs. However, the molecular mechanisms mediating these two cellular processes remain largely unknown. Recently, several studies provide new insights into p38 and JNK MAPK pathways function in the control of the balance of autophagy and apoptosis in response to genotoxic stress. Our increased understanding of the role of p38 and JNK MAPK pathways in regulating the balance of autophagy and apoptosis will hopefully provide prospective strategies for cancer therapy.

[1]  B. Zhivotovsky,et al.  miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence , 2012, British Journal of Cancer.

[2]  Hai-Yan Zhou,et al.  Resveratrol protects H9c2 embryonic rat heart derived cells from oxidative stress by inducing autophagy: role of p38 mitogen-activated protein kinase. , 2012, Canadian journal of physiology and pharmacology.

[3]  L Bibbs,et al.  A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. , 1994, Science.

[4]  Ashok Kumar,et al.  Inhibition of N-(4-hydroxyphenyl)retinamide-induced autophagy at a lower dose enhances cell death in malignant glioma cells. , 2007, Carcinogenesis.

[5]  Tao Xi,et al.  E Platinum, a newly synthesized platinum compound, induces autophagy via inhibiting phosphorylation of mTOR in gastric carcinoma BGC-823 cells. , 2012, Toxicology letters.

[6]  J. Woodgett,et al.  The stress-activated protein kinase subfamily of c-Jun kinases , 1994, Nature.

[7]  A. Cuadrado,et al.  Mechanisms and functions of p38 MAPK signalling. , 2010, The Biochemical journal.

[8]  Xiaofeng Zhu,et al.  c-Jun NH2-terminal kinase activation is essential for up-regulation of LC3 during ceramide-induced autophagy in human nasopharyngeal carcinoma cells , 2011, Journal of Translational Medicine.

[9]  Jiahuai Han,et al.  The p38 signal transduction pathway: activation and function. , 2000, Cellular signalling.

[10]  Hongjuan You,et al.  HBx activates FasL and mediates HepG2 cell apoptosis through MLK3-MKK7-JNKs signal module. , 2012, World journal of gastroenterology.

[11]  P. Picci,et al.  Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines. , 2012, Molecular bioSystems.

[12]  A. Causse,et al.  Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma. , 2011, Cancer research.

[13]  P. Cohen,et al.  Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. , 2000, The Biochemical journal.

[14]  L. Cai,et al.  Knockdown of osteopontin chemosensitizes MDA-MB-231 cells to cyclophosphamide by enhancing apoptosis through activating p38 MAPK pathway. , 2011, Cancer biotherapy & radiopharmaceuticals.

[15]  M. Červinka,et al.  Selenite-induced apoptosis and autophagy in colon cancer cells. , 2012, Toxicology in vitro : an international journal published in association with BIBRA.

[16]  Ashok Kumar,et al.  Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress. , 2006, Carcinogenesis.

[17]  Jui‐I Chao,et al.  Regulation of gamma-H2AX and securin contribute to apoptosis by oxaliplatin via a p38 mitogen-activated protein kinase-dependent pathway in human colorectal cancer cells. , 2008, Toxicology letters.

[18]  R. Sánchez-Prieto,et al.  Autop38-phagy and apop38-tosis in genotoxic stress: A strange duo , 2012, Autophagy.

[19]  James R. Woodgett,et al.  Phosphorylation of c-jun mediated by MAP kinases , 1991, Nature.

[20]  Yaoh-Shiang Lin,et al.  Quercetin Suppresses Drug-Resistant Spheres via the p38 MAPK–Hsp27 Apoptotic Pathway in Oral Cancer Cells , 2012, PloS one.

[21]  Daniel E. Johnson,et al.  Bortezomib induces autophagy in head and neck squamous cell carcinoma cells via JNK activation. , 2012, Cancer letters.

[22]  B. Guerra,et al.  Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells , 2012, International journal of oncology.

[23]  B. Liagre,et al.  The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells. , 2012, Biochimie.

[24]  Hyung-Ryong Kim,et al.  p38 Mitogen-activated protein kinase is involved in endoplasmic reticulum stress-induced cell death and autophagy in human gingival fibroblasts. , 2010, Biological & pharmaceutical bulletin.

[25]  S. S. Koh,et al.  Cancer upregulated gene 2, a novel oncogene, confers resistance to oncolytic vesicular stomatitis virus through STAT1-OASL2 signaling , 2013, Cancer Gene Therapy.

[26]  T. Ikejima,et al.  Oridonin induced autophagy in human cervical carcinoma HeLa cells through Ras, JNK, and P38 regulation. , 2007, Journal of pharmacological sciences.

[27]  C. Simone Signal-Dependent Control of Autophagy and Cell Death in Colorectal Cancer Cell: The Role of the p38 Pathway , 2007 .

[28]  R. Deng,et al.  Upregulation of sestrin 2 expression via JNK pathway activation contributes to autophagy induction in cancer cells. , 2013, Cellular signalling.

[29]  Jemma L. Webber,et al.  Coordinated regulation of autophagy by p38α MAPK through mAtg9 and p38IP , 2010, The EMBO journal.

[30]  Joseph Avruch,et al.  Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. , 2012, Physiological reviews.

[31]  B. Hill,et al.  Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response☆ , 2013, Redox biology.

[32]  K. Sabapathy Role of the JNK pathway in human diseases. , 2012, Progress in molecular biology and translational science.

[33]  Fulvio Chiacchiera,et al.  Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models. , 2012, Cancer letters.

[34]  Enlong Ma,et al.  JNK-dependent Atg4 upregulation mediates asperphenamate derivative BBP-induced autophagy in MCF-7 cells. , 2012, Toxicology and applied pharmacology.

[35]  D. Xing,et al.  Bcl‐2 and Bcl‐xL play important roles in the crosstalk between autophagy and apoptosis , 2011, The FEBS journal.

[36]  Qibing Zhou,et al.  Inhibition of the met receptor tyrosine kinase signaling enhances the chemosensitivity of glioma cell lines to CDDP through activation of p38 MAPK pathway , 2009, Molecular Cancer Therapeutics.

[37]  L. Ellis,et al.  Mechanisms of Anti-Angiogenic Tyrosine Kinase Inhibition on Wound Healing: The Obvious and Not So Obvious , 2002, Cancer biology & therapy.

[38]  K. Schulze-Osthoff,et al.  Phosphorylation of Atg5 by the Gadd45β–MEKK4-p38 pathway inhibits autophagy , 2012, Cell Death and Differentiation.

[39]  S. Yeh,et al.  Cross‐talk of alpha tocopherol‐associated protein and JNK controls the oxidative stress‐induced apoptosis in prostate cancer cells , 2013, International journal of cancer.

[40]  B. Nico,et al.  A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells , 2007, Cell Death and Differentiation.

[41]  R. Deng,et al.  The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells , 2009, Oncogene.

[42]  B. G. Sanders,et al.  Critical roles for JNK, c‐Jun, and Fas/FasL‐Signaling in vitamin E analog‐induced apoptosis in human prostate cancer cells , 2008, The Prostate.

[43]  B. Levine,et al.  Dual Role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation , 2008, Autophagy.

[44]  Zhiheng Xu,et al.  JNK pathway: diseases and therapeutic potential , 2007, Acta Pharmacologica Sinica.

[45]  D. Rubinsztein,et al.  Bim Inhibits Autophagy by Recruiting Beclin 1 to Microtubules , 2012, Molecular cell.

[46]  Huibi Xu,et al.  Resistance to docetaxel‐induced apoptosis in prostate cancer cells by p38/p53/p21 signaling , 2011, The Prostate.

[47]  P. Codogno,et al.  Evidence for the interplay between JNK and p53-DRAM signaling pathways in the regulation of autophagy , 2010, Autophagy.

[48]  Lin Zhao,et al.  Gene Silencing of FANCF Potentiates the Sensitivity to Mitoxantrone through Activation of JNK and p38 Signal Pathways in Breast Cancer Cells , 2012, PloS one.

[49]  H. Schaeffer,et al.  Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers , 1999, Molecular and Cellular Biology.

[50]  M. Diederich,et al.  ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis. , 2012, Carcinogenesis.

[51]  Fugeng Sheng,et al.  The heme oxygenase-1 inhibitor ZnPPIX induces non-canonical, Beclin 1-independent, autophagy through p38 MAPK pathway. , 2012, Acta biochimica et biophysica Sinica.

[52]  A. Thorburn,et al.  Autophagy and Cancer Therapy , 2014, Molecular Pharmacology.

[53]  S. Dakshanamurthy,et al.  Tyrosine-phosphorylated Caveolin-1 (Tyr-14) Increases Sensitivity to Paclitaxel by Inhibiting BCL2 and BCLxL Proteins via c-Jun N-terminal Kinase (JNK)* , 2012, The Journal of Biological Chemistry.

[54]  P. Codogno,et al.  c-Jun NH2-terminal kinase activation is essential for DRAM-dependent induction of autophagy and apoptosis in 2-methoxyestradiol-treated Ewing sarcoma cells. , 2009, Cancer research.

[55]  Joel I. Pritchard,et al.  BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect , 2003, Nature Medicine.

[56]  T. Ikejima,et al.  TNFα-induced necroptosis and autophagy via supression of the p38-NF-κB survival pathway in L929 cells. , 2011, Journal of pharmacological sciences.

[57]  Fugeng Sheng,et al.  The heme oxygenase-1 inhibitor ZnPPIX induces non-canonical , Beclin 1-independent , autophagy through p 38 MAPK pathway , 2012 .

[58]  C. Terry,et al.  Triterpenes From Ganoderma Lucidum Induce Autophagy in Colon Cancer Through the Inhibition of p38 Mitogen-Activated Kinase (p38 MAPK) , 2010, Nutrition and cancer.

[59]  Jing-Yuan Fang,et al.  The MAPK signalling pathways and colorectal cancer. , 2005, The Lancet. Oncology.

[60]  J. Olson,et al.  p38 MAP kinase: a convergence point in cancer therapy. , 2004, Trends in molecular medicine.

[61]  F. Althaus,et al.  Cell Death and Autophagy under Oxidative Stress: Roles of Poly(ADP-Ribose) Polymerases and Ca2+ , 2012, Molecular and Cellular Biology.

[62]  Jemma L. Webber Regulation of autophagy by p38α MAPK , 2010 .

[63]  D. Hommes,et al.  Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets , 2003, Gut.

[64]  I. Chu,et al.  Histone deacetylase 6 functions as a tumor suppressor by activating c‐Jun NH2‐terminal kinase‐mediated beclin 1‐dependent autophagic cell death in liver cancer , 2012, Hepatology.

[65]  Yung-Hyun Choi,et al.  Rottlerin induces apoptosis of HT29 colon carcinoma cells through NAG-1 upregulation via an ERK and p38 MAPK-dependent and PKC δ-independent mechanism. , 2012, Chemico-biological interactions.

[66]  Yong J. Lee,et al.  The Role of Bcl-xL in Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia on Human Colon Cancer , 2012, Molecular Cancer Research.

[67]  E. Ashry,et al.  Quinuclidinone derivative 6 induced apoptosis in human breast cancer cells via sphingomyelinase and JNK signaling , 2012, Journal of chemotherapy.

[68]  R. Kurzrock,et al.  Autophagy as a target for anticancer therapy , 2011, Nature Reviews Clinical Oncology.

[69]  Guan Chen,et al.  The p38 MAPK stress pathway as a tumor suppressor or more? , 2008, Frontiers in bioscience : a journal and virtual library.

[70]  Ryan J H West,et al.  Oxidative stress and autophagy , 2012, Autophagy.

[71]  A. Causse,et al.  MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy , 2012, Autophagy.

[72]  Shan Zhu,et al.  HMGB1 regulates autophagy through increasing transcriptional activities of JNK and ERK in human myeloid leukemia cells. , 2011, BMB reports.

[73]  A. Cuenda,et al.  p38 MAP-kinases pathway regulation, function and role in human diseases. , 2007, Biochimica et biophysica acta.

[74]  J. Blank,et al.  p38 Mitogen-activated protein kinase mediates cell death and p21-activated kinase mediates cell survival during chemotherapeutic drug-induced mitotic arrest. , 2003, Molecular biology of the cell.

[75]  Yung-Hyun Choi,et al.  Induction of apoptosis in human colon cancer HCT-116 cells by anthocyanins through suppression of Akt and activation of p38-MAPK. , 2009, International journal of oncology.

[76]  A. Cuadrado,et al.  p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. , 2007, Cancer cell.

[77]  Raymond Sawaya,et al.  The role of autophagy in cancer development and response to therapy , 2005, Nature Reviews Cancer.

[78]  G. Mills,et al.  Sustained Activation of JNK/p38 MAPK Pathways in Response to Cisplatin Leads to Fas Ligand Induction and Cell Death in Ovarian Carcinoma Cells* , 2003, Journal of Biological Chemistry.

[79]  Gabriella De Vita,et al.  p38α MAP Kinase as a Sensor of Reactive Oxygen Species in Tumorigenesis , 2007 .

[80]  Johannes Rinn,et al.  Ras/Erk MAPK Signaling in Epidermal Homeostasis and Neoplasia , 2007, Cell cycle.

[81]  P. Rakic,et al.  Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene , 1997, Nature.

[82]  R. Sánchez-Prieto,et al.  P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance , 2012, Oncogene.

[83]  M. Czaja,et al.  Macroautophagy and chaperone‐mediated autophagy are required for hepatocyte resistance to oxidant stress , 2010, Hepatology.

[84]  Cheol‐Hee Kim,et al.  Inhibition of MKK7-JNK by the TOR signaling pathway regulator-like protein contributes to resistance of HCC cells to TRAIL-induced apoptosis. , 2012, Gastroenterology.

[85]  Byung-Hoon Lee,et al.  Proteasome inhibition-induced p38 MAPK/ERK signaling regulates autophagy and apoptosis through the dual phosphorylation of glycogen synthase kinase 3β. , 2012, Biochemical and biophysical research communications.

[86]  K. Ryan,et al.  The role of autophagy in tumour development and cancer therapy , 2009, Expert Reviews in Molecular Medicine.

[87]  H. Nishina,et al.  Involvement of JNK in the regulation of autophagic cell death , 2010, Oncogene.

[88]  B. Liu,et al.  c-Jun N-terminal kinase is required for thermotherapy-induced apoptosis in human gastric cancer cells. , 2012, World journal of gastroenterology.

[89]  Kazuhiro Nakamura,et al.  The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. , 2007, Biochimica et biophysica acta.

[90]  G. Ingravallo,et al.  p38α blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1α- to FoxO-dependent transcription , 2009, Cell Death and Differentiation.

[91]  Haowei Song,et al.  Group VIA PLA2 (iPLA2β) Is Activated Upstream of p38 Mitogen-activated Protein Kinase (MAPK) in Pancreatic Islet β-Cell Signaling* , 2011, The Journal of Biological Chemistry.

[92]  Ke Gong,et al.  P38 MAP kinase functions as a switch in MS-275-induced reactive oxygen species-dependent autophagy and apoptosis in human colon cancer cells. , 2012, Free radical biology & medicine.

[93]  Andrew D Sharrocks,et al.  MAP kinase signalling cascades and transcriptional regulation. , 2013, Gene.

[94]  Nobuyuki Tanaka,et al.  Mechanism of p38 MAP kinase activation in vivo. , 2003, Genes & development.