Sham S. Kakar, Ph.D.


Sham S. Kakar, Ph.D.
sskaka01@louisville.edu
Kurukshetra University
1983


Professor
Department of Physiology,
Department of Medicine,
Department of Biochemistry and Molecular Biology,
Division of Endocrinology and Metabolism,
Division of Medical Oncology,
and Brown Cancer Center.


RESEARCH

Cancer, Drug Discovery and Molecular Mechanisms of Disease

Our major/main research interest is to understand the molecular mechanism of causation and prevention of hormone related cancers. Drug investigation and the membrane signaling transduction mechanism in the regulation of cellular functions. We are working on two research projects: 1) Development of Targeted Therapy for Cancer Treatment. The primary treatment modality for cancer is cytoreductive surgery followed by adjuvant chemotherapy, radiotherapy, or both. This strategy is successful in the majority of patients, however it is always accompanied by cytotoxicity to normal organ and tissues and multidrug resistance (MDR). Ideally, therapeutic agents should be selectively targeted to cancerous cells to avoid systemic toxicities. Such targeting may be effected by forming an adduct between a cytotoxic agent and a tumor-specific ligand. Our work extends this adduct paradigm to studies of nanoparticles (NPs) targeted to the luteinizing hormone-releasing hormone (LHRH) receptor, which is overexpressed in variety of cancers. We hypothesize that targeting the LHRH receptor using LHRH and doxorubicin-conjugated (DOX) gold NPs will enhance particle uptake by cancer cells and lead to selective tumor cell killing without related systemic cytotoxicity. 2) Molecular mechanisms of pituitary tumor transforming gene (PTTG) in human tumorigenesis. PTTG is a potent oncogene and is found to be highly expressed in most of the tumors analyzed to date. Its overespression in normal cells leads to cellular transformation and development of tumors in nude mice. Our research work is focused to understand the mechanisms, by which PTTG mediates its tumorigenic function, determine the three dimensional structure and utilize PTTG as a target gene in the development of specific small molecules to target PTTG gene for the treatment of cancer.

RECENT PUBLICATIONS

  1. Panguluri SK, Kakar SS (2012) Using quantitative real-time reverse transcriptase polymerase chain reaction to validate gene regulation by PTTG. Methods Mol Biol. 815:131-45.
  2. Fong MY, Jin S, Gupta R, Rane M and Kakar SS (2012) Withaferin A enhances the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer. PLoS One. 7(7):e42265.
  3. Kakar SS and Fong MY (2012) Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines.  Biochem Biophys Res Commun. 423: 819-825.
  4. Fong MY, Farghaly HI and Kakar SS (2012) Tumorigenic potential of pituitary tumor transforming gene (PTTG) in vivo investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/) transgenic mice. BMC Cancer. 12: 532.
  5. Fong MY, McDunn J and Kakar SS (2013) Mass spectrometry for the identification of global metabolomics in ovarian carcinomas. Methods Mol Biol. 1049:239-53.
  6. Ratajczak MZ, Jadczyk T, Schneider G, Kakar SS and Kucia MJ (2013) Induction of a tumor-metastasis-receptive microenvironment as an unwanted and underestimated side effect of treatment by chemotherapy or radiotherapy. J Ovarian Res. 6(1):95.
  7. Beach A, Huang-Ge Zhang H-G, Mariusz Z Ratajczak MZ and Kakar SS (2014) Exosomes: An overview of biogenesis, composition and role in ovarian cancer. J Ovarian Res. 7:14
  8. Macha MA, Rachagani S, Pai P, Gupta S, Lydiatt WM, Smith RB, Johansson SL, Lele SM, Kakar SS, Lee JH, Meza J, Ganti AK, Jain M, Batra SK (2014) MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene. 10.1038/onc.2014.102. [Epub ahead of print]
  9. Ratajczak MZ, Schneider G, Sellers ZP, Kuria M and Kakar SS (2014) The embryonic rest hypothesis of cancer development- an XIX century theory revised. J Cancer Stem Cell Research. 2:e10001.
  10. Mu J, Zhuang X, Wang Q, Jiang H, Deng ZB, Wang B, Zhang L, Kakar S, Jun Y, Miller D, Zhang HG (2014) Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol Nutr Food Res. 2014 Jul; 58(7):1561-73.
  11. Suszynska M, Poniewierska-Baran A, Gunjal P, Ratajczak J, Marycz K, Kakar SS, Kucia M, Ratajczak MZ (2014) Expression of the erythropoietin receptor by germline-derived cells - further support for a potential developmental link between the germline and hematopoiesis. J Ovarian Res. 7:66.
  12. Kakar SS, Ratajczak MZ, Powell KS, Moghadamfalahi M, Miller DM and Singh SK (2014) Withaferin A alone as well as in combination with ciplatin suppresses tumor growth and metastasis by targeting cancer stem cell population in ovarian cancer. PLoS One. 9 (9):e107596.
  13. Mierzejewska1 K, Borkowska S, Suszynska1 E, Suszynska M, Poniewierska A, Maj M, Pedziwiatr P, Kakar SS, Ratajczak J, Kucia M1 and  Mariusz Z. Ratajczak MZ (2015). Hematopoietic stem/progenitor cells express several functional sex hormone receptors - novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. Stem Cells Dev. Jan 21. [Epub ahead of print]
  14. Kakar SS and Kakar C (2015) Generation of Transgenic Mouse Model Using PTTG as an Oncogene. Methods Mol Biol. 1267:395-411.
  15. Gunjal PM, Schneider G, Ismail AA, Kakar SS, Kucia M, Ratajczak MZ (2015) Evidence for induction of a tumor metastasis-receptive microenvironment for ovarian cancer cells in bone marrow and other organs as an unwanted and underestimated side effect of chemotherapy/radiotherapy. J Ovarian Res. 8:20.
  16. Macha MA, Rachagani S, Pai P, Gupta S, Lydiatt WM, Smith RB, Johansson SL, Lele SM, Kakar SS, Farghaly H, Lee JH, Meza J, Ganti AK, Jain M, Batra SK (2015) MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene. 34(21):2814.
  17. Gunjal P, Pedziwiatr D, Ismail AA, Kakar SS, Ratajczak MZ (2015) An emerging question about putative cancer stem cells in established cell lines-are they true stem cells or a fluctuating cell phenotype? J Cancer Stem Cell Res. 3. pii: e1004.
  18. Abdelbaset-Ismail A, Pedziwiatr D, Suszyńska E, Sluczanowska-Glabowska S, Schneider G, Kakar SS, Ratajczak MZ (2016) Vitamin D3 stimulates embryonic stem cells but inhibits migration and growth of ovarian cancer and teratocarcinoma cell lines. J Ovarian Res. 9:26.
  19. Kakar SS, Worth CA, Wang Z, Carter K, Ratajczak M, Gunjal P (2016) DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer. J Cancer Stem Cell Res. 2016;4. pii: e1002.
  20. Kakar SS, Parte S, Carter K, Joshua IG, Worth C, Rameshwar, P and Ratajczak MZ (2017). Withaferin A (WFA) inhibits cancer growth and metastasis by targeting ovarian cancer stem cells. Oncotarget. 8: 74494-74505.
  21. Schneider G, Sellers ZP, Bujko K, Kakar SS, Kucia M, Ratajczak MZ (2017) Novel pleiotropic effects of bioactive phospholipids in human lung cancer metastasis. Oncotarget. 8:58274-58263.   
  22. Bliss SA, Paul S, Pobiarzyn PW, Ayer S, Pant S, Hilton H, Sharma N, Cunha, MF, Engelberth DJ,  Greco SJ, Bryan M, Kucia MJ, Kakar SS, Ratajczak MZ and  Rameshwar P (2017) Working breast cancer cell hierarchy in treatment response and long-term outcome. Sci Rep. Submitted.
  23. Carter K, Rameshwar P, Ratajczak MZ and Kakar SS (2017) Verrucarin J inhibits ovarian cancer and targets cancer stem cells. Oncotarget. In Press.
  24. Parte S, Smolenkov A, Batra SK, Ratajczak MZ and Kakar SS (2017) Ovarian Cancer Stem Cells: Unravelling a Germline Connection. Stem Cell Dev. Revision submitted.
  25. Parte S, Ratajczak MZ and Kakar SS (2017) Etiology of cancer stem cells with stages of ovarian cancer. Submitted.
  26. Kakar SS, Ratajczak MZ and Virant-Klun Irma (2017) Co-expression of securin and cancer stem cell markers in ovarian ascites and mechanisms of self-renewal. In preparation.
  27. Utoh K, Carter K and Kakar SS (2017) Verrucarin J target cancer stem cells through the inhibition of WNT1/β-catenin signaling pathway in lung cancer. In preparation.